Efficient Synthesis Of Morphine And Codeine

ABSTRACT

The present invention relates to methods for the synthesis of morphine, intermediates, salts and derivatives thereof. In preferred embodiments, the invention relates to methods for improving the efficiency and overall yield of said morphine, morphine related derivatives and intermediates thereof. In further embodiments, the invention relates to methods for improving the efficiency and overall yield of galanthamine and intermediates thereof.

FIELD OF THE INVENTION

The present invention relates to methods for the synthesis of morphineand precursors, intermediates, and derivatives thereof. In preferredembodiments, the invention relates to methods for improving theefficiency and overall yield of said morphine, morphine relatedderivatives and intermediates thereof. In further embodiments, theinvention relates to methods for improving the efficiency and overallyield of galanthamine and intermediates thereof.

BACKGROUND OF THE INVENTION

Morphine is one of the most important analgesics worldwide. The majorityof the world's morphine supply is derived from poppy plants found insome of the more politically turbulent areas of western Asia. A relatedcompound, galanthamine, has shown efficacy in the treatment of, interalia, Alzheimer's disease. However, while morphine remains in highdemand worldwide, the lack of effective synthetic methods coupled withthe aforementioned instability in areas largely responsible for thenatural production of morphine illustrates the tenuous state of currentmeans for obtaining the compound. Similarly, overall yields forgalanthamine using current synthetic routes remain poor. Thus, there isa need to develop improved methods for synthesizing morphine and relatedderivatives for use in pharmaceutical compositions and other medicalapplications.

SUMMARY OF THE INVENTION

The present invention relates to methods and compositions for thesynthesis of galanthamine, morphine and precursors, intermediates(including but not limited to codeine), salts, and derivatives thereof.In addition, pharmaceutical formulations comprising such compositions,as well as methods of treatment comprising administering saidcompositions), are contemplated. In preferred embodiments, the inventionrelates to methods for improving the efficiency and overall yield ofsaid morphine, morphine related derivatives and intermediates thereof,as well as the resulting compositions for pharmaceutical formulationsand human treatment (e.g. to relieve or prevent pain, to suppresscoughing, etc.). In further embodiments, the invention relates tomethods for improving the efficiency and overall yield of galanthamineand intermediates thereof, as well as the resulting compositions forpharmaceutical formulations and human treatment (e.g. mild to moderateAlzheimer's). In addition, the methods permit the further efficientsynthesis of galanthamine derivatives, such as N-alkyl galanthaminederivatives [e.g. N-allylnorgalanthamine,N-(14-methylallyl)norgalanthamine, etc., see FIG. 10], which are morepotent cholinesterase inhibitors than galanthamine.

In addition, atoms making up the compounds of the present invention areintended to include all isotopic forms of such atoms. Isotopes, as usedherein, include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium, and isotopes of carboninclude ¹³C and ¹⁴C. Similarly, it is contemplated that one or morecarbon atom(s) of a compound of the present invention may be replaced bya silicon atom(s). Furthermore, it is contemplated that one or moreoxygen atom(s) of a compound of the present invention may be replaced bya sulfur or selenium atom(s).

Other non-carbon groups contemplated by the present invention ascandidates for substituting into the compounds described herein include,but are not limited to oxy, amino, amido, imino, thio, thiol, sulfonyl,ammonium, sulfonium, silyl and the substituted versions of these groups.

In some embodiments the terms alkyl, aryl, alkanediyl, alkynyl,arenediyl, aralkyl, heteroarenediyl, heteroaralkyl, heteroaryl, alkenyl,alkenediyl, alkynediyl, acyl, alkylidene, or a substituted version ofany of these groups, refer to groups with a number of carbons≦20. Insome embodiments the terms alkyl, aryl, alkanediyl, alkynyl, arenediyl,aralkyl, heteroarenediyl, heteroaralkyl, heteroaryl, alkenyl,alkenediyl, alkynediyl, acyl, alkylidene, or a substituted version ofany of these groups, refer to groups with a number of carbons≦12. Insome embodiments the terms alkyl, aryl, alkanediyl, alkynyl, arenediyl,aralkyl, heteroarenediyl, heteroaralkyl, heteroaryl, alkenyl,alkenediyl, alkynediyl, acyl, alkylidene, or a substituted version ofany of these groups refer to groups with a number of carbons≦10. In someembodiments the terms alkyl, aryl, alkanediyl, alkynyl, arenediyl,aralkyl, heteroarenediyl, heteroaralkyl, heteroaryl, alkenyl,alkenediyl, alkynediyl, acyl, alkylidene, or a substituted version ofany of these groups, refer to groups with a number of carbons≦8. In someembodiments, the present invention contemplates allyl, propargyl, andcyclopropyl carbinol derivatives.

In some embodiments (FIG. 3A), the invention relates to a method forforming a cross-conjugated 2,5-cyclohexadienone, comprising i) providinga substituted biphenyl; ii) treating said biphenyl to create an ether.In further embodiments, said biphenyl is treated with an alkenylether orvinylether (e.g. ethylvinyl ether) under a set of conditions to create abiphenyl ether. In one embodiment, the method further comprises iii)treating said ether under conditions (e.g. with a phenol alkylatingcatalyst) to cause intramolecular phenol alkylation so as to produce across-conjugated 2,5-cyclohexadienone (or derivative thereof). Infurther embodiments, said substituted biphenyl is produced in a Suzukicoupling reaction. In still further embodiments, said substitutedbiphenyl is produced in an Ullman coupling reaction. In still furtherembodiments said substituted biphenyl ether is treated under a secondset of conditions to form a cross-conjugated 2,5-cyclohexadienonederivative. Some generic embodiments are shown in FIG. 3A. Some specificnon-limiting examples of contemplated derivatives are shown in FIG. 3B.In additional embodiments, said substituted biphenyl has the structure:

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl or heteroaryl groupor the like (i.e. other groups such as alkanediyl, alkynyl, arenediyl,aralkyl, heteroarenediyl, heteroaralkyl, alkenyl, alkenediyl,alkynediyl, acyl, alkylidene, non-carbon group, or a substituted versionof any of these groups), a protecting group, but not H, and R₂ is aprotecting group or H. In some embodiments, said protecting group isselected from the group consisting of triisopropylsilyl andtert-butyldimethylsilyl. In further embodiments, said ether has thestructure:

wherein Z is H or R₁), wherein R₁ is an alkyl, aryl, or heteroaryl groupor the like a protecting group but not H; R₂ is a protecting group or H;R₆ can be alkyl or aryl or the like (i.e. other groups such asalkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl, heteroaralkyl,heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl, alkylidene,non-carbon group, or a substituted version of any of these groups); andX is a halide or an equivalent leaving group. Some generic embodimentsare shown in FIG. 3A. Some specific non-limiting examples ofcontemplated derivatives are shown in FIG. 3B. In further embodiments,said cross-conjugated 2,5-cyclohexadienone has the structure:

wherein R₁ is an alkyl, aryl, or heteroaryl group or the like or aprotecting group but not H; and R₆ is a protecting group or H. At thispoint, the synthesis can be directed to galanthamine or to morphine (thesteps leading to morphine will be described here and the steps leadingto galanthamine will be described below). In one embodiment where thesynthesis proceeds to morphine, the method further comprises iv)treating the cross-conjugated 2,5-cyclohexadienone of step iii) with anitroalkane under Henry reaction conditions so as to create adihydro-1H-phenanthren-2-one derivative. In additional embodiments, saiddihydro-1H-phenanthren-2-one derivative is a nitroalkene. In additionalembodiments, said dihydro-1H-phenanthren-2-one derivative is a β-hydroxynitroalkane. Some generic embodiments are shown in FIG. 4A. Somespecific non-limiting examples of contemplated derivatives are shown inFIG. 4B. In some embodiments, said nitroalkene has the structure

wherein R₁ is an alkyl, aryl or heteroaryl group or the like or aprotecting group but not H; and R₆ can be alkyl or aryl or the like(i.e. other groups such as alkanediyl, alkynyl, arenediyl, aralkyl,heteroarenediyl, heteroaralkyl, heteroaryl, alkenyl, alkenediyl,alkynediyl, acyl, alkylidene, non-carbon group, or a substituted versionof any of these groups). Some generic embodiments are shown in FIG. 4A.Some specific non-limiting examples of contemplated derivatives areshown in FIG. 4B. In some embodiments, said nitroalkane has thestructure

wherein R₁ is an alkyl, aryl or heteroaryl group or the like or aprotecting group but not H; R₆ can be alkyl or aryl or the like, and R₇can be H, alkyl, aryl, or heteroaryl group or the like (i.e. othergroups such as alkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl,heteroaralkyl, heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl,alkylidene, non-carbon group, or a substituted version of any of thesegroups). In further embodiments, said dihydro-1H-phenanthren-2-onederivative is in the form of a mixture of epimers. In some embodiments,the invention further comprises v) treating said nitroalkene with a(mild) reducing agent so as to create nitroalkane. Some genericembodiments are shown in FIG. 4A. Some specific non-limiting examples ofcontemplated derivatives are shown in FIG. 4B. It is noteworthy thatonly the correct cis-stereochemical relationship between the newlyformed B-ring and the C-ring, i.e. at the C₁₃ and C₁₄ positions, isobserved in 15. In further embodiments, said nitroalkane has thestructure

wherein R₁ is an alkyl, aryl, or heteroaryl group or a protecting groupbut not H; R₆ can be alkyl or aryl or the like; and R₇ can be H, alkyl,aryl, heteroaryl group or the like. In still further embodiments, saidnitroalkane is in the form of a mixture of epimers. In additionalembodiments, the invention further comprises vi) treating saidnitroalkane with a reducing agent so as to create a primary amine. Somegeneric embodiments are shown in FIG. 4A. Some specific non-limitingexamples of contemplated derivatives are shown in FIG. 4B. In someembodiments, said amine has the structure

wherein R₁ is an alkyl, aryl, or heteroaryl group or the like or aprotecting group but not H; R₆ can be alkyl/aryl or the like; and R₇ canbe H, alkyl, aryl, heteroaryl group or the like. In some embodiments,the invention further comprises vii) treating said primary amine with a(mild) reducing agent so as to create a secondary amine. In furtherembodiments, said secondary amine is the result of intramolecularreductive amination. Some generic embodiments are shown in FIG. 4A. Somespecific non-limiting examples of contemplated derivatives are shown inFIG. 4B. In still further embodiments, said secondary amine has thestructure

wherein R₁ is an alkyl, aryl, or heteroaryl group or the like, aprotecting group or H; and R₇ can be H or an alkyl, aryl, or heteroarylgroup or the like. In additional embodiments, the invention furthercomprises viii) treating said secondary amine with base so as to createa carbamate derivative. Some generic embodiments are shown in FIG. 4A.Some specific non-limiting examples of contemplated derivatives areshown in FIG. 4B. In some embodiments, said carbamate derivative has thestructure

wherein R₁ is an alkyl, aryl, heteroaryl group or the like, a protectinggroup, or H; R₇ is H or an alkyl, aryl, or heteroaryl group or the like;and R₈ is an alkyl, aryl, or heteroaryl group or the like (i.e. othergroups such as alkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl,heteroaralkyl, heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl,alkylidene, non-carbon group, or a substituted version of any of thesegroups). In further embodiments, the invention further comprises ix)treating said carbamate derivative with a halohydantoin so as to createa halohydrin. In still further embodiments, said halohydantoin is 2,2bromo-3,5 dimethylhydantoin and said halohydrin is a bromohydrin. Somegeneric embodiments are shown in FIG. 5A. Some specific non-limitingexamples of contemplated derivatives are shown in FIG. 5B. In additionalembodiments, said bromohydrin has the structure

wherein R₁ is an alkyl, aryl, or heteroaryl group or the like, aprotecting group or H; R₇ is H or an alkyl, aryl, or heteroaryl group orthe like; and R₈ is an alkyl, aryl, or heteroaryl group or the like.

In additional embodiments, the invention further comprises viii)treating said secondary amine with carbon-halide so as to create atertiary amine derivative. Some generic embodiments are shown in FIG.4A. Some specific non-limiting examples of contemplated derivatives areshown in FIG. 4B. In some embodiments, said tertiary amine derivativehas the structure

wherein R₁ is an alkyl, aryl, heteroaryl group or the like, a protectinggroup, or H; R₇ is H or an alkyl, aryl, or heteroaryl group or the like;and R₈ is an alkyl, aryl, or heteroaryl group or the like (i.e. othergroups such as alkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl,heteroaralkyl, heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl,alkylidene, non-carbon group, or a substituted version of any of thesegroups).

In some embodiments, further comprising x) treating said halohydrin withbase so as to create an epoxide. Some generic embodiments are shown inFIG. 5A. Some specific non-limiting examples of contemplated derivativesare shown in FIG. 5B. In further embodiments, said epoxide has thestructure

wherein R₁ is an alkyl, aryl, or heteroaryl group or the like or aprotecting group, or H; R₇ is H or an alkyl, aryl, or heteroaryl groupor the like; R₈ is an alkyl, aryl, or heteroaryl group or the like; andX is a halide or an equivalent leaving group. This epoxide is a novelcompound and an important compound, since it allows access to a largerange of derivatives (including but not limited to 7-alkyl (or aryl,etc.) derivatives of codeine); the present invention contemplates this6,7-alpha-epoxide as a composition of matter and in methods forsynthesizing downstream derivatives (including but not limited to7β-substituted 7,8-dihydro derivatives) as pharmaceutical formulationsfor human treatment. Some specific non-limiting examples of contemplatedderivatives are shown in FIG. 9B. In still further embodiments, theinvention further comprises xi) treating said epoxide with a reducingagent in the presence of an organic disulfide so as to create a carbosulfide. Some generic embodiments are shown in FIG. 5A. Some specificnon-limiting examples of contemplated derivatives are shown in FIG. 5B.In additional embodiments, said carbo sulfide has the structure

wherein R₁ is an alkyl, aryl, or heteroaryl group or the like, or aprotecting group, or H; R₇ is an H or an alkyl, aryl, or heteroarylgroup or the like; R₈ is an alkyl, aryl, or heteroaryl group or thelike; R₉ is an alkyl, aryl, or heteroaryl group or the like (i.e. othergroups such as alkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl,heteroaralkyl, heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl,alkylidene, non-carbon group, or a substituted version of any of thesegroups); and X is a halide or an equivalent leaving group. In stillfurther embodiments, the invention further comprises xi) treating saidepoxide with a reducing agent in the presence of an organic disulfide soas to create a phenyl sulfide. Some generic embodiments are shown inFIG. 5A. Some specific non-limiting examples of contemplated derivativesare shown in FIG. 5B. In additional embodiments, said phenyl sulfide hasthe structure

wherein R₁ is an alkyl, aryl, or heteroaryl group or the like, or aprotecting group, or H; R₇ is an H or an alkyl, aryl, or heteroarylgroup or the like; R₈ is an alkyl, aryl, or heteroaryl group or thelike; and X is a halide or an equivalent leaving group. In additionalembodiments, the invention further comprises xii) treating saidphenylsulfide with an oxidizing agent (preferably hydrogen peroxide) inthe presence of an acidic alcohol such as a halogenated alcohol(preferably hexafluoroisopropanol) so as to create a sulfoxide. Somegeneric embodiments are shown in FIG. 9A. Some specific non-limitingexamples of contemplated derivatives are shown in FIG. 9B. In oneembodiment, said sulfoxide has the structure:

wherein R₁ is an alkyl, aryl, or heteroaryl group or the like, or aprotecting group, or H; R₇ is an H or an alkyl, aryl, or heteroarylgroup or the like; R₈ is an alkyl, aryl, or heteroaryl group or thelike; R₉ is an alkyl, aryl, or heteroaryl group or the like; and X is ahalide or an equivalent leaving group. In further embodiments, theinvention further comprises xiii) heating said sulfoxide to give anallylic alcohol. Some generic embodiments are shown in FIG. 5A. Somespecific non-limiting examples of contemplated derivatives are shown inFIG. 5B. In some embodiments, said allylic alcohol has the structure

wherein R₁ is an alkyl, aryl, or heteroaryl group or the like, or aprotecting group, or H; R₇ is an H or an alkyl, aryl, or heteroarylgroup or the like; R₈ is an alkyl, aryl, or heteroaryl group or thelike; and X is a halide or an equivalent leaving group. In furtherembodiments, the invention further comprises xiv) treating said allylicalcohol with a reducing agent so as to create codeine. In still furtherembodiments, the invention further comprises xv) treating said codeinewith a (preferably strong) Lewis acid so as to create morphine.

In still further embodiments, the invention further comprises treatingsaid epoxide with a Grignard reagent so as yield an epoxide ring opened6-hydroxy,7-adduct. Some generic embodiments are shown in FIG. 9A. Somespecific non-limiting examples of contemplated derivatives are shown inFIG. 9B. In additional embodiments, said epoxide ring opened6-hydroxy,7-adduct has the structure

wherein R₁ is an alkyl, aryl, or heteroaryl group or the like, or aprotecting group, or H; R₇ is an H or an alkyl, aryl, or heteroarylgroup or the like; R₈ is an alkyl, aryl, or heteroaryl group or the likeR₁₀ is an alkyl, aryl, or heteroaryl group or the like (i.e. othergroups such as alkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl,heteroaralkyl, heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl,alkylidene, non-carbon group, or a substituted version of any of thesegroups) or H; and X is a halide or an equivalent leaving group.

In some embodiments, the invention relates to a composition of theformula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, or heteroaryl groupor the like or a protecting group, but not H; R₂ is a protecting group.In one embodiment, the protecting group is selected from a groupconsisting of triisopropylsilyl and tert-butyldimethylsilyl, and (ingeneral) SiR₃R₄R₅ where R₃ can be alkyl, aryl, or the like (i.e. othergroups such as alkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl,heteroaralkyl, heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl,alkylidene, non-carbon group, or a substituted version of any of thesegroups), R₄ can be alkyl, aryl, or the like (i.e. other groups such asalkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl, heteroaralkyl,heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl, alkylidene,non-carbon group, or a substituted version of any of these groups), andR₅ can be alkyl, aryl, or the like (i.e. other groups such asalkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl, heteroaralkyl,heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl, alkylidene,non-carbon group, or a substituted version of any of these groups). Infurther embodiments, the inventions relates to a composition of theformula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, or heteroaryl groupor the like or a protecting group, but not H; R₂ is a protecting groupor H; R₆ can be alkyl or aryl or the like; and X is a halide or anequivalent leaving group. In still further embodiments, the inventionrelates to a composition of the formula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, heteroaryl group orthe like, or a protecting group, or H; and R₆ is a protecting group. Inadditional embodiments, the invention relates to a composition of theformula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, heteroaryl group orthe like or a protecting group, or H; and R₆ can be alkyl or aryl or thelike (i.e. other groups such as alkanediyl, alkynyl, arenediyl, aralkyl,heteroarenediyl, heteroaralkyl, heteroaryl, alkenyl, alkenediyl,alkynediyl, acyl, alkylidene, non-carbon group, or a substituted versionof any of these groups). In some embodiments, the invention relates to acomposition of the formula (or salt thereof).

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, heteroaryl group orthe like or a protecting group, or H; R₆ can be alkyl, aryl or the like;and R₇ can be H, alkyl, aryl, or heteroaryl group or the like. Infurther embodiments, the invention relates to a composition of theformula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, heteroaryl group orthe like or a protecting group, or H; R₆ can be alkyl, aryl, or thelike; and R₇ can be H, alkyl, aryl or heteroaryl group, or the like. Instill further embodiments, the invention relates to a composition of theformula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, heteroaryl group orthe like or a protecting group, or H; R₆ can be alkyl, aryl, or thelike; and R₇ can be H, alkyl, aryl, or heteroaryl group or the like. Inadditional embodiments, the invention relates to a composition of theformula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, heteroaryl group orthe like or a protecting group, or H; and R₇ can be H or an alkyl, aryl,or heteroaryl group, or the like. In some embodiments, the inventionrelates to a composition of the formula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, or heteroaryl groupor the like or a protecting group, or H; R₇ is H or an alkyl, aryl, orheteroaryl group or the like; and R₈ is an alkyl, aryl, or heteroarylgroup or the like. In further embodiments, the invention relates to acomposition of the formula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, or heteroaryl groupor the like or a protecting group, or H; R₇ is H or an alkyl, aryl, orheteroaryl group or the like; R₈ is an alkyl, aryl, or heteroaryl groupor the like; and X is a halide or an equivalent leaving group. In stillfurther embodiments, the invention relates to a composition of theformula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, or heteroaryl groupor the like or a protecting group, or H; R₇ is H or an alkyl, aryl, orheteroaryl group or the like; R₈ is an alkyl, aryl, or heteroaryl groupor the like; and X is a halide or an equivalent leaving group. Inadditional embodiments, the invention relates to a composition of theformula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, or heteroaryl groupor the like or a protecting group, or H; R₇ is H or an alkyl, aryl, orheteroaryl group or the like; R₈ is an alkyl, aryl, or heteroaryl groupor the like; R₉ is an alkyl, aryl, or heteroaryl group or the like; andX is a halide or an equivalent leaving group. In some embodiments, theinvention relates to a composition of the formula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, or heteroaryl groupor the like or a protecting group, or H; R₇ is H or an alkyl, aryl, orheteroaryl group or the like; R₈ is an alkyl, aryl, or heteroaryl groupor the like; R₉ is an alkyl, aryl, or heteroaryl group or the like; andX is a halide or an equivalent leaving group. In further embodiments,the invention relates to a composition of the formula (or salt thereof):

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl, or heteroaryl groupor the like or a protecting group or H, or H; R₇ is H or an alkyl, aryl,or heteroaryl group or the like; R₈ is an alkyl, aryl, or heteroarylgroup or the like; and X is a halide or an equivalent leaving group. Instill further embodiments, the invention relates to a composition of theformula (or salt thereof):

In additional embodiments, the invention relates to a composition of theformula (or salt thereof):

In some embodiments, the invention relates to a method of synthesizing acompound comprising: mixing 4-bromophenol, imidazole and1,2-dichloroethane at a temperature between 20° C. and 25° C.,preferably 23° C., to form a first solution, mixingtriisopropylsilylchloride with said first solution for at least 10hours, preferably at least 11 hours and more preferably 12 hours, toform a second mixture, transferring said second mixture to an aqueousNH₄Cl to form a third solution, combining said third solution withCH₂Cl₂ to form a fourth solution, combining said fourth solution with abrine solution to form a fifth solution, mixing said fifth solution withNa₂SO₄, separating said fifth solution from said Na₂SO₄ to give a sixthsolution, reducing the volume of said sixth solution using a means forreducing said volume, and recovering said compound. In furtherembodiments, said means for reducing volume is a vacuum system. In stillfurther embodiments, said compound is:

In further embodiments, R is selected from the group consisting of -TIPS(triisopropylsilyl) and -TBDMS (tert-butyldimethylsilyl). In additionalembodiments, the percent yield of said compound is at least 95%,preferably at least 97% and more preferably 99%.

In some embodiments, the invention relates to a method of synthesizing acompound comprising: mixing isovanillin, anhydrous sodium acetate, ironpowder, glacial acetic acid and argon gas to form a first solution,combining a bromine solution further comprising acetic acid with saidfirst solution to form a second solution, combining said second solutionwith water maintained at a temperature between 0° C. and 10° C. to forma third solution, filtering said third solution, reducing the volume ofsaid third solution using a means for reducing said volume, andrecovering said compound. In further embodiments, said means forreducing volume is a vacuum system. In still further embodiments, saidcompound is:

In additional embodiments, the percent yield of said compound is atleast 75%, preferably at least 77% and more preferably 79% or more.

In some embodiments, the invention further comprises: mixing(4-bromo-phenoxy)-triisopropylsilane and THF at a temperature of atleast −75° C., preferably −78° C. to form a first solution, mixing saidfirst solution with a composition comprising n-BuLi further comprisingTHF to form a second solution, stirring said second solution for atleast 60 minutes, preferably 70 minutes, at a temperature of at least−75° C., more preferably −78° C., mixing said second solution with asolution of B(OPr^(i))₃ to form a third solution, stirring said thirdmixture for at least 10 hours, preferably at least 11 hours and morepreferably 12 hours, at a temperature of at least 20° C., preferably 23°C., mixing said third mixture with a solution comprising 10% aqueousKHSO₄ to form a fourth solution, mixing said fourth solution with EtOActo form a fifth solution, mixing said fifth solution with a brinesolution to form a sixth solution, i) mixing said sixth solution withNa₂SO₄, reducing the volume of said sixth solution using a means forusing a means for reducing said volume to obtain a first solid,purifying said first solid using a first means for purification to forma second solid, mixing said second solid with toluene, and recoveringsaid compound. In further embodiments, said means for reducing volume isa vacuum system. In still further embodiments, said compound is:

In even further embodiments, Ar is:

In additional embodiments, the percent yield of said compound is atleast 75%, preferably 76% or more.

In some embodiments, the invention further comprises: mixing1,4-dioxane, water, K₂CO₃, 2,6-di-tert-butyl-4 methylphenol, andtricyclohexylphoshine to form a first solution, stirring said firstsolution for at least 10 minutes, preferably 15 minutes at a temperatureof at least 20° C., preferably 23° C., mixing said first solution with[Pd₂(dba)₃] to form a second solution, refluxing said second solutionfor at least 45 minutes, preferably 55 minutes and more preferably 60minutes, mixing said second solution with aqueous NH₄Cl to form a thirdsolution, mixing said third solution with EtOAc to form a fourthsolution, mixing said fourth solution with a brine solution to form afifth solution, mixing said fifth solution with Na₂SO₄, separating saidfifth solution from said Na₂SO₄, reducing the volume of said fifthsolution using a means for reducing said volume, and recovering saidcompound. In further embodiments, said means for reducing volume is avacuum system. In still further embodiments, said compound is:

In additional embodiments, R is TIPS. In some embodiments, the percentyield of said compound is at least 85%, preferably at least 95% and morepreferably 96%. In some embodiments, the invention relates to a methodfor synthesizing a compound comprising: mixing bromine and CH₂Cl₂ at atemperature of 0° C. to form a first solution, mixing said firstsolution with ethyl vinyl ether to form a second solution, stirring saidsecond solution for at least 15 minutes, preferably 20 minutes, at 0°C., mixing said second solution with N,N-diisopropylamine to form athird solution, mixing said third solution with a mixture comprisingCH₂Cl₂ to form a fourth solution, stirring said fourth solution for atleast 10 hours, preferably at least 11 hours and more preferably 12hours, at a temperature of at least 20° C., more preferably 23° C.,mixing said fourth solution with saturated aqueous NaHCO₃ to form afifth solution, mixing said fifth solution with CH₂Cl₂ to form a sixthsolution, mixing said sixth solution with a brine solution to form aseventh solution, mixing said seventh solution with Na₂SO₄, separatingsaid seventh solution from said Na₂SO₄, reducing the volume of saidseventh solution using a means for reducing said volume, and recoveringsaid compound. In further embodiments, said means for reducing volume isa vacuum system. In still further embodiments, said compound is:

In additional embodiments, R is TIPS. In some embodiments, the percentyield of said compound is at least 95%, preferably at least 97% and morepreferably at least 99%.

In some embodiments, the invention further comprises: mixing CsF and DMFto form a first solution, refluxing said first solution for at least onehour, mixing said first mixture with saturated aqueous NaHCO₃ to form asecond mixture, mixing said second mixture with EtOAc to form a thirdmixture, mixing said third solution with a brine solution to form afourth solution, mixing said fourth solution with Na₂SO₄, separatingsaid fourth solution from said Na₂SO₄, reducing the volume of saidfourth solution using a means for reducing said volume, and recoveringsaid compound. In further embodiments, said means for reducing volume isa vacuum system. In further embodiments, said compound is:

In still further embodiments, the percent yield of said compound is atleast 80%, preferably at least 85% and more preferably 90% or more.

In some embodiments, the invention further comprises: addingnitromethane to form a first solution, mixing NH₄OAc and acetic acidwith said first solution to form a second solution, refluxing saidsecond solution for at least one hour, preferably two hours, mixing saidsecond solution with a brine solution to form a third solutioncomprising an aqueous layer and a non-aqueous layer, removing saidaqueous layer from said third solution, mixing said aqueous layer withether to form a fourth solution, mixing said fourth layer with Na₂SO₄,separating said fourth layer from said Na₂SO₄, reducing the volume ofsaid fourth solution using a means for reducing said volume, andrecovering said mixture of compounds. In further embodiments, said meansfor reducing volume is a vacuum system. In still further embodiments,said mixture of compounds comprises:

In additional embodiments, the percent yield of said mixture ofcompounds is at least 50%, preferably 90% and more preferably 97% ormore.

In some embodiments, the invention further comprises: mixing THF andphosphate buffer to form a first solution, mixing said first solutionwith NaBH₃CN at a temperature of 0° C. to form a second solution,stirring said second solution for at least 30 minutes, preferably 45minutes and more preferably 60 minutes, mixing said second solution withaqueous NH₄Cl to form a third solution, mixing said third solution withEtOAc to form a fourth solution, mixing said fourth solution with abrine solution to form a fifth solution, mixing said fifth solution withNa₂SO₄, separating said fifth solution from said Na₂SO₄, reducing thevolume of said fifth solution using a means for reducing said volume,and recovering said mixture of compounds. In further embodiments, saidmeans for reducing volume is a vacuum system. In still furtherembodiments, said mixture of compounds comprises:

In additional embodiments, the percent yield of said mixture ofcompounds is at least 80%, preferably at least 85% and more preferablyat least 88%. In some embodiments, the invention further comprises:mixing THF and an argon atmosphere to form a first solution, coolingsaid first solution to a temperature of at least −75° C., preferably−78° C., mixing said first solution with LiAlH₄ to form a secondsolution, stirring said second solution at a temperature of at least−75° C., preferably −78° C., for at least 30 minutes, preferably atleast 45 minutes and more preferably 60 minutes, raising the temperatureof said second solution to at least 20° C. over a time period of atleast six hours, preferably at least seven hours and more preferablyeight hours, mixing said second solution with aqueous Na₂SO₄ at atemperature of 0° C. to form a first salt, mixing said first salt withether to form a third solution, filtering said third solution using ameans for filtering, mixing said third solution with a brine solution toform a fourth solution, combining said fourth solution with Na₂SO₄,separating said fourth solution from said Na₂SO₄, reducing the volume ofsaid fourth solution using a means for reducing said volume, andrecovering said mixture of compounds. In further embodiments, said meansfor reducing volume is a vacuum system. In still further embodiments,said mixture of compounds comprises:

In additional embodiments, the overall percent yield of said mixture ofcompounds is at least 70% and preferably 72% or more.

In some embodiments, the invention further comprises: mixing dioxane toform a first solution, mixing said first solution with HCl to form asecond solution, stirring said second solution for at least 5 minutes,preferably 10 minutes, mixing said second solution with NaCNBH₃ to forma third solution, refluxing said third solution for at least threehours, preferably at least four hours and more preferably five hours,cooling said third solution to a temperature of at least 20° C., mixingsaid third solution with diethyl ether and NaOH to form a fourthsolution, mixing said fourth solution with a brine solution to form afifth solution, separating said fifth solution from said Na₂SO₄,reducing the volume of said fifth solution using a means for reducingsaid volume, and recovering said compound. In further embodiments, saidmeans for reducing volume is a vacuum system. In still furtherembodiments, said compound is:

In additional embodiments, the overall yield of said compound is atleast 60%, preferably at least 65% and more preferably 66% or more. Insome embodiments, the invention relates to a method for synthesizing acompound comprising: mixing CH₂Cl₂ to form a first solution, reducingthe temperature of said first solution to 0° C., mixing said firstsolution with triethylamine and ethyl chloroformate to form a secondsolution, stirring said second solution at a temperature of 0° C. for atleast 30 minutes, preferably 60 minutes, mixing said second solutionwith saturated aqueous NH₄Cl to form a third solution, mixing said thirdsolution with CH₂Cl₂ to form a fourth solution, mixing said fourthsolution with a brine solution to form a fifth solution, mixing saidfifth solution with Na₂SO₄, separating said fifth solution from saidNa₂SO₄, reducing the volume of said fifth solution using a means forreducing said volume, and recovering said compound. In furtherembodiments, said means for reducing volume is a vacuum system. In stillfurther embodiments, said compound is:

In additional embodiments, the overall yield of said compound is atleast 85%, preferably at least 89% or more.

In some embodiments, the invention relates to a method for synthesizinga compound comprising: mixing CH₂Cl₂ to form a first solution, reducingthe temperature of said first solution to 0° C., mixing said firstsolution with methylbromide to form a second solution, stirring saidsecond solution at a temperature of 0° C. for at least 30 minutes,preferably 60 minutes<reducing the volume of said fifth solution using ameans for reducing said volume, and recovering said compound. In furtherembodiments, said means for reducing volume is a vacuum system. In stillfurther embodiments, said compound is:

In some embodiments, the invention further comprises: mixing acetone andH₂O to form a first solution, mixing said first solution with2,2-bromo-3,5-dimethylhydantoin over a period of at least 3 minutes toform a second solution, covering said second solution using a means forcovering, stirring said second solution for at least 10 hours,preferably at least 11 hours and more preferably 12 hours, mixing saidsecond solution with saturated NH₄Cl to form a third solution, mixingsaid third solution with water to form a fourth solution, mixing saidfourth solution with ethyl acetate to form a fifth solution, mixing saidfifth solution with a brine solution to form a sixth solution, mixingsaid sixth solution with Na₂SO₄, separating said sixth solution fromsaid Na₂SO₄, reducing the volume of said sixth solution using a meansfor reducing said volume, and recovering said compound. In furtherembodiments, said means for reducing volume is a vacuum system. In stillfurther embodiments, said means for covering comprises an aluminum foilsheet. In additional embodiments, said compound is:

In some embodiments, the overall yield of said compound is at least 95%,preferably 97% or more.

In some embodiments, the invention further comprises: mixing toluene toform a first solution, mixing said first solution with KOH to form asecond solution, heating said second solution at a temperature of atleast 70° C., preferably at least 75° C. and more preferably 80° C., fora time period of at least 2 hours, preferably 3 hours, reducing thetemperature of said second solution, mixing said second solution withwater to form a third solution, mixing said third solution with ethylacetate to form a fourth solution, mixing said fourth solution with abrine solution to form a fifth solution, mixing said fifth solution withNa₂SO₄, separating said fifth solution from said Na₂SO₄, reducing thevolume of said fifth solution using a means for reducing said volume,recovering a crude extract comprising said compound, and purifying saidcrude extract. In further embodiments, said means for reducing volume isa vacuum system. In still further embodiments, said compound is:

In additional embodiments, the overall yield of said compound is atleast 90%, preferably at least 95% or more.

In some embodiments, the invention relates to a method for synthesizinga compound comprising: mixing diphenyl disulfide and ethanol to form afirst solution, mixing said first solution with NaBH₄ over a time periodof at least 3 minutes, preferably 5 minutes, to form a second solution,stirring said second solution for at least 10 minutes, preferably 15minutes, mixing said second solution and ethanol to form a thirdsolution, stirring said third solution at a temperature of at least 20°C. for a time period of at least 1 hour, preferably 2 hours, mixing saidthird solution with water to form a fourth solution, mixing said fourthsolution with CH₂Cl₂ to form a fifth solution, mixing said fifthsolution with a brine solution to form a sixth solution, mixing saidsixth solution with Na₂SO₄, separating said sixth solution from saidNa₂SO₄, reducing the volume of said sixth solution using a means forreducing said volume, and recovering said compound. In furtherembodiments, said means for reducing volume is a vacuum system. In stillfurther embodiments, said compound is:

In additional embodiments, the overall yield of said compound is atleast 95%, preferably at least 97% and more preferably 99%. In someembodiments, the invention further comprises: mixinghexafluoroisopropanol to form a first solution, mixing said firstsolution with hydrogen peroxide to form a second solution, stirring saidsecond solution for a time period of at least 10 minutes, preferably 15minutes, mixing said second solution with water to form a thirdsolution, mixing said third solution with saturated aqueous Na₂SO₃ toform a fourth solution, mixing said fourth solution with CH₂Cl₂ to forma fifth solution, mixing said fifth solution with a brine solution toform a sixth solution, mixing said sixth solution with Na₂SO₄,separating said sixth solution from said Na₂SO₄, reducing the volume ofsaid sixth solution using a means for reducing said volume, andrecovering said compound. In further embodiments, said means forreducing volume is a vacuum system. In still further embodiments, saidcompound is:

In additional embodiments, the overall yield of said compound is atleast 80%, preferably at least 90%, and more preferably 93% or more.

In some embodiments, the invention further comprises: mixing THF to forma first solution, mixing said first solution with LiAlH₄ to form asecond solution, stirring said second solution at a temperature of atleast 20° C. for a time period of at least 4 hours, preferably at least5 hours and more preferably 6 hours, reducing the temperature of saidsecond solution to 0° C., mixing said second solution with saturatedaqueous Na₂SO₄ to form a third solution, filtering said third solutionwith Celite, mixing said third solution with diethyl ether to form afourth solution, mixing said fourth solution with Na₂SO₄, separatingsaid fourth solution from said Na₂SO₄, reducing the volume of saidfourth solution using a means for reducing said volume, and recoveringsaid compound. In further embodiments, said means for reducing volume isa vacuum system. In still further embodiments, said compound is:

In additional embodiments, the overall yield of said compound is atleast 80%, preferably at least 85% and more preferably 87% or more. Insome embodiments, the invention further comprises: mixing chloroform toform a first solution, mixing said first solution with boron tribromideto form a second solution, stirring said second solution at atemperature of at least 20° C. for a time period of at least 15 minutes,preferably 20 minutes, mixing said second solution with NH₄OH at atemperature of 0° C. to form a third solution, mixing said thirdsolution with a mixture of CH₂Cl₂ and ethanol to form a fourth solution,mixing said fourth solution with a brine solution to form a fifthsolution, mixing said fifth solution with Na₂SO₄, separating said fifthsolution from said Na₂SO₄, reducing the volume of said fifth solutionusing a means for reducing said volume to produce an extract, mixingsaid extract with a composition comprising SiO₂, CH₂Cl₂ and ethanol, andrecovering said compound. In further embodiments, said means forreducing volume is a vacuum system. In still further embodiments, saidcompound is:

In additional embodiments, the overall yield of said compound is atleast 80%, preferably at least 85% and more preferably 86% or more.

In some embodiments, the invention further comprises: mixing HCl anddioxane to form a first solution, refluxing said first solution toproduce a first compound, mixing said first compound with a compositioncomprising MeNH₂, THF, NaBH(OAc)₃ and AcOH at a temperature of at least50° C., preferably 60° C., to produce a second compound, and mixing saidsecond compound with L-Selectride under conditions such that a thirdcompound is produced. In further embodiments, said first compound is:

In still further embodiments, said second compound is:

In additional embodiments, said third compound is:

In some embodiments, the overall yield of said first compound is atleast 85% or more. In further embodiments, the overall yield of saidsecond compound is at least 65% or more. In still further embodiments,the overall yield of said third compound is at least 55% or more.

In one embodiment, the invention relates to improved methods for thesynthesis of galanthamine, derivatives, salts and intermediates thereof.Galanthamine((4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4-aH-[1]benzofuro[3a,3,2-ef]-[2]-benzazepin-6-ol;C₁₇H₂₁NO₃; MW=287), an amaryllidaceae alkaloid. In one embodiment, thecompound is contemplated for early treatment of Alzheimer's disease. Asnoted above, in one embodiment, the present invention contemplates thatthe early synthesis steps for morphine and galanthamine are shared (e.g.up to the formation of the cross-conjugated 2,5-cyclohexadienone). Asnoted above, the synthesis can thereafter go in the direction ofmorphine (the steps for which have been described above) orgalanthamine, intermediates, derivatives and salts thereof (the stepsfor which are described below). For example, in some embodiments wherethe synthesis is directed towards galanthamine, the present inventionfurther comprises: treating the cross-conjugated 2,5-cyclohexadienonewith acid under conditions to cause acid catalyzed hydrolysis of saidcross-conjugated 2,5-cyclohexadienone so as to form an aldehyde-lactol,said aldehyde lactol comprising a acyl (carbonyl) group. In a preferredembodiment, said cross-conjugated 2,5-cyclohexadienone is:

wherein R₁ is an alkyl, aryl or heteroaryl group or the like or aprotecting group but not H; R₆ is an alkyl, aryl or heteroaryl group orthe like or a protecting group but not H. In still further embodiments,said aldehyde-lactol compound is:

wherein R₁ is an alkyl, aryl or heteroaryl group or the like or aprotecting group. In some embodiments, the invention further comprises:treating said aldehyde-lactol under conditions such that said acyl(carbonyl) group is converted to an amine by reductive amination so asto form (±) narwedine (including but not limited to an N-alkyl, aryl,heteroaryl, allyl, cyclopropyl carbinol, or n-propargyl derivativethereof).

In some embodiments, the invention further comprises: wherein (±)narwedine is formed sequentially in the same reaction after theformation of a first intermediate, followed by a second intermediate. Insome embodiments, the invention further comprises: wherein a narwedinederivative is formed sequentially in the same reaction after theformation of a first intermediate, followed by a second intermediate. Insome embodiments, the invention further comprises wherein said firstintermediate is an amino-lactol (including but not limited to anN-alkyl, aryl, heteroaryl, allyl, cyclopropyl carbinol, or n-propargylderivative thereof). In still further embodiments, said compound is:

wherein R₁ is an alkyl, aryl or heteroaryl group or the like or aprotecting group; R₁₁ is an alkyl, aryl or heteroaryl group or the like(i.e. other groups such as alkanediyl, alkynyl, arenediyl, aralkyl,heteroarenediyl, heteroaralkyl, heteroaryl, alkenyl, alkenediyl,alkynediyl, acyl, alkylidene, methyl, allyl, cyclopropyl, carbinol,n-propargyl, non-carbon group, or a substituted version of any of thesegroups) or a protecting group or H.In some embodiments, the invention further comprises wherein said secondintermediate is a carbinolamine ether (a “hemiaminal”) (including butnot limited to an N-alkyl, aryl, heteroaryl, allyl, cyclopropylcarbinol, or n-propargyl derivative thereof). In still furtherembodiments, said compound is:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups or a protecting group, or H; and R₁₁ is an alkyl,aryl or heteroaryl group or the like (i.e. other groups such asalkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl, heteroaralkyl,heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl, alkylidene, methyl,allyl, cyclopropyl, carbinol, n-propargyl, non-carbon group, or asubstituted version of any of these groups) or a protecting group or H.In still further embodiments, said (±) narwedine has the structure:

In some embodiments, said narwedine derivative has the structure:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups or a protecting group, or H; and R₁₁ is an alkyl,aryl or heteroaryl group or the like (i.e. other groups such asalkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl, heteroaralkyl,heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl, alkylidene, Methyl,allyl, cyclopropyl, carbinol, n-propargyl, non-carbon group, or asubstituted version of any of these groups) or a protecting group or H.In some embodiments, the invention further comprises: reducing saidnarwedine derivative to a galanthamine derivative with a reducing agent.Some generic embodiments are shown in FIG. 7A. Some specificnon-limiting examples of contemplated derivatives are shown in FIG. 7B.Some specific non-limiting examples of contemplated derivatives areshown in FIG. 7C. In some embodiments, said galanthamine derivative hasthe structure:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups or a protecting group, or H; and R₁₁ is an alkyl,aryl or heteroaryl group or the like (i.e. other groups such asalkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl, heteroaralkyl,heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl, alkylidene, methyl,allyl, cyclopropyl, carbinol, n-propargyl, non-carbon group, or asubstituted version of any of these groups) or a protecting group or H.In some embodiments, said a galanthamine derivative isN-(14-methylallyl)norgalanthamine. In some embodiments, said agalanthamine derivative is N-(14-methylallyl)norgalanthamine has thestructure:

In some embodiments, said a galanthamine derivative isN-allylnorgalanthamine. In some embodiments, said a galanthaminederivative is N-allylnorgalanthamine has the structure:

In some embodiments, said a galanthamine derivative is Norgalanthamine.In some embodiments, said a galanthamine derivative is Norgalanthaminehas the structure:

In some embodiments, the invention further comprises: resolving said (±)narwedine into (−)-narwedine in the presence of galanthamine. In stillfurther embodiments, said resolving is in the presence of 1%(+)-galanthamine. In still further embodiments, further comprisingresolving said (±) narwedine into (−)-narwedine in the presence ofgalanthamine with a reducing agent. While it is not intended that thepresent invention be limited by the nature of the reducing agent, in apreferred embodiment, said reducing agent is L-Selectride. Reduction of(−)-narwedine with L-Selectride provides (−)-galanthamine (99%).

As noted above, the methods permit the further efficient synthesis ofgalanthamine derivatives, such as N-alkyl galanthamine derivatives [e.g.N-allylnorgalanthamine, N-(14-methylallyl)norgalanthamine, some specificnon-limiting examples of contemplated derivatives are shown in thestructures in FIG. 10], which are more potent cholinesterase inhibitorsthan galanthamine. In this regard, the above-described steps can bemodified to create these derivatives. Moreover, the present inventioncontemplates treating and/or preventing disease with galanthamine (andderivatives thereof) synthesized according to the above scheme andformulated as pharmaceutical formulations.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures.

FIG. 1 shows a biosynthetic pathway for the synthesis of morphine andcodeine.

FIG. 2 shows embodiments of the present invention, as well as the atomicnumbering scheme for morphine.

FIGS. 3 A and B show embodiments of the present invention forsynthesizing a cross-conjugated compound useful in the synthesis of bothmorphine and galanthamine (as well as derivatives of both). FIG. 3Aprovides the general overall scheme, while FIG. 3B provides specific(non-limiting) examples.

FIGS. 4 A and B show embodiments of the present invention whereby across-conjugated compound is modified in a series of steps (andalternative pathways) to create a carbamate and tertiary aminederivatives useful for the synthesis of morphine and derivativesthereof. FIG. 4A provides the general overall scheme, while FIG. 4Bprovides specific (non-limiting) examples.

FIGS. 5 A and B show embodiments of the present invention whereby acarbamate derivative is modified in a series of steps to generatemorphine, derivatives thereof, and related compounds (e.g. codeine).FIG. 5A provides the general overall scheme, while FIG. 5B providesspecific (non-limiting) examples.

FIG. 6 shows the atomic numbering scheme for galanthamine and thestructural similarity of narwedine.

FIGS. 7 A and B show embodiments of the present invention whereby across-conjugated compound is modified in a series of steps so as tosynthesis narwedine and galanthamine. FIG. 7A provides the generaloverall scheme, while FIG. 7B provides specific (non-limiting) examples.Compounds 2, 14, 24, 25 and 26 are racemates, but the structures aredrawn in FIG. 7B (for clarity) as a single enantiomer with theirconfiguration corresponding to that of (−)-galanthamine. FIG. 7Cprovides specific (non-limiting) examples. FIG. 7C provides analternative synthetic route for the production of narwedine andgalanthamine. Compounds 2, 14, 24, and 27 are racemates, but thestructures are drawn in FIG. 7C (for clarity) as a single enantiomerwith their configuration corresponding to that of (−)-galanthamine.

FIGS. 8 A and B show embodiments of the present invention wherebycertain R₇ derivatives of the cross-conjugate can be made. FIG. 8Aprovides the general overall scheme, while FIG. 8B provides specific(non-limiting) examples.

FIGS. 9 A and B show embodiments of the present invention wherein anovel epoxide is used to make useful downstream derivatives (includingbut not limited to 7-β substituted 7,8-dihydro derivatives). FIG. 9Aprovides the general overall scheme, while FIG. 9B provides specific(non-limiting) examples.

FIG. 10 shows the structure of some specific non-limiting examples ofgalanthamine derivatives, such as N-alkyl galanthamine derivatives [e.g.N-allylnorgalanthamine, N-(14-methylallyl)norgalanthamine, thestructures for which are shown in FIG. 10].

DEFINITIONS

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

As used herein, “cross-conjugated” refers to a compound where in thereare (at least) two double bonds that are conjugated to a “central”double bond in such a way that the π electronic system forms abifurcation.

As used herein, “morphine” refers to a compound represented by thefollowing chemical structure:

where R is H. It is not intended that the invention be limited to anyparticular derivative, analog or isomer of morphine or salt thereof.Examples of derivatives of morphine include but are in no way limited tomorphine, morphine acetate, morphine citrate, morphine bitartrate,morphine stearate, morphine phthalate, morphine hydrobromide, morphinehydrobromide.2H₂O, morphine hydrochloride, morphine hydrochloride.3H₂O,morphine hydriodide.2H₂O, morphine lactate, morphine monohydrate,morphine meconate.5H₂O, morphine mucate, morphine nitrate, morphinephosphate.0.5H₂O, morphine phosphate.7H₂O, morphine salicylate, morphinephenylpropionate, morphine methyliodide, morphine isobutyrate, morphinehypophosphite, morphine sulfate.5H₂O, morphine tannate, morphinetartrate.3H₂O, morphine valerate, morphine methylbromide, morphinemethylsulfonate, morphine-N-oxide, morphine-N-oxide quinate,dihydromorphine and pseudomorphine. It is not intended that the presentinvention be limited by the type of chemical substituent or substituentsthat is or are coordinated to morphine. Examples of chemicalsubstituents include but are in no way limited to hydrogen, methyl,ethyl, formyl, acetyl, phenyl, chloride, bromide, hydroxyl, methoxyl,ethoxyl, methylthiol, ethylthiol, propionyl, carboxyl, methoxy carbonyl,ethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl,butylthiocarbonyl, dimethylcarbamyl, diethylcarbamyl,N-piperidinylcarbonyl, N-methyl-N′-piperazinylcarbonyl,2-(dimethylamino)ethylcarboxy, N-morpholinylcarbonyl,2-(dimethylamino)ethylcarbamyl, 1-piperidinylcarbonyl, methylsulfonyl,ethylsulfonyl, phenylsulfonyl, 2-piperidinylethyl, 2-morpholinylethyl,2-(dimethylamino)ethyl, 2-(diethyl amino) ethyl, butylthiol,dimethylamino, diethylamino, piperidinyl, pyrrolidinyl, imidazolyl,pyrazolyl, N-methylpiperazinyl and 2-(dimethylamino)ethylamino.

As used herein, “codeine” refers to a compound represented by thefollowing chemical structure:

where R is CH₃, also referred to as a methyl (Me) substituent. It is notintended that the invention be limited to any particular derivative,analog or isomer of codeine or salt thereof. Examples of derivatives ofcodeine include but are in no way limited to codeine, codeine acetate,codeine citrate, codeine bitartrate, codeine stearate, codeinephthalate, codeine hydrobromide, codeine hydrobromide.2H₂O, codeinehydrochloride, codeine hydrochloride.3H₂O, codeine hydriodide.2H₂O,codeine lactate, codeine monohydrate, codeine meconate.5H₂O, codeinemucate, codeine nitrate, codeine phosphate.0.5H₂O, codeinephosphate.7H₂O, codeine salicylate, codeine phenylpropionate, codeinemethyliodide, codeine isobutyrate, codeine hypophosphite, codeinesulfate.5H₂O, codeine tannate, codeine tartrate.3H₂O, codeine valerate,codeine methylbromide, codeine methylsulfonate, codeine-N-oxide,codeine-N-oxide quinate and pseudocodeine. It is not intended that thepresent invention be limited by the type of chemical substituent orsubstituents that is or are coordinated to codeine. Examples of chemicalsubstituents include but are in no way limited to hydrogen, methyl,ethyl, formyl, acetyl, phenyl, chloride, bromide, hydroxyl, methoxyl,ethoxyl, methylthiol, ethylthiol, propionyl, carboxyl, methoxy carbonyl,ethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl,butylthiocarbonyl, dimethylcarbamyl, diethylcarbamyl,N-piperidinylcarbonyl, N-methyl-N′-piperazinylcarbonyl,2-(dimethylamino)ethylcarboxy, N-morpholinylcarbonyl,2-(dimethylamino)ethylcarbamyl, 1-piperidinylcarbonyl, methylsulfonyl,ethylsulfonyl, phenylsulfonyl, 2-piperidinylethyl, 2-morpholinylethyl,2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, butylthiol,dimethylamino, diethylamino, piperidinyl, pyrrolidinyl, imidazolyl,pyrazolyl, N-methylpiperazinyl and 2-(dimethylamino)ethylamino.

As used herein, “galanthamine” refers to a compound represented by thefollowing chemical structure:

It is not intended that the invention be limited to any particularderivative, analog or isomer of galanthamine or salt thereof. Examplesof derivatives of galanthamine include but are in no way limited togalanthamine, galanthamine acetate, galanthamine citrate, galanthaminebitartrate, galanthamine stearate, galanthamine phthalate, galanthaminehydrobromide, galanthamine hydrobromide.2H₂O, galanthaminehydrochloride, galanthamine hydrochloride.3H₂O, galanthaminehydriodide.2H₂O, galanthamine lactate, galanthamine monohydrate,galanthamine meconate.5H₂O, galanthamine mucate, galanthamine nitrate,galanthamine phosphate. 0.5H₂O, galanthamine phosphate.7H₂O,galanthamine salicylate, galanthamine phenylpropionate, galanthaminemethyliodide, galanthamine isobutyrate, galanthamine hypophosphite,galanthamine sulfate.5H₂O, galanthamine tannate, galanthaminetartrate.3H₂O, galanthamine valerate, galanthamine methylbromide,galanthamine methylsulfonate, galanthamine-N-oxide, galanthamine-N-oxidequinate and pseudogalanthamine. It is not intended that the presentinvention be limited by the type of chemical substituent or substituentsthat is or are coordinated to galanthamine. Examples of chemicalsubstituents include but are in no way limited to hydrogen, methyl,ethyl, formyl, acetyl, phenyl, chloride, bromide, hydroxyl, methoxyl,ethoxyl, methylthiol, ethylthiol, propionyl, carboxyl, methoxy carbonyl,ethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl,butylthiocarbonyl, dimethylcarbamyl, diethylcarbamyl,N-piperidinylcarbonyl, N-methyl-N′-piperazinylcarbonyl,2-(dimethylamino)ethylcarboxy, N-morpholinylcarbonyl,2-(dimethylamino)ethylcarbamyl, 1-piperidinylcarbonyl, methylsulfonyl,ethylsulfonyl, phenylsulfonyl, 2-piperidinylethyl, 2-morpholinylethyl,2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, butylthiol,dimethylamino, diethylamino, piperidinyl, pyrrolidinyl, imidazolyl,pyrazolyl, N-methylpiperazinyl and 2-(dimethylamino)ethylamino.

As used herein, “narwedine” refers to a compound represented by thefollowing chemical structure:

It is not intended that the invention be limited to any particularderivative, analog or isomer of narwedine or salt thereof. Examples ofderivatives of narwedine include but are in no way limited to narwedine,narwedine acetate, narwedine citrate, narwedine bitartrate, narwedinestearate, narwedine phthalate, narwedine hydrobromide, narwedinehydrobromide.2H₂O, narwedine hydrochloride, narwedinehydrochloride.3H₂O, narwedine hydriodide.2H₂O, narwedine lactate,narwedine monohydrate, narwedine meconate.5H₂O, narwedine mucate,narwedine nitrate, narwedine phosphate.0.5H₂O, narwedine phosphate.7H₂O,narwedine salicylate, narwedine phenylpropionate, narwedinemethyliodide, narwedine isobutyrate, narwedine hypophosphite, narwedinesulfate.5H₂O, narwedine tannate, narwedine tartrate.3H₂O, narwedinevalerate, narwedine methylbromide, narwedine methylsulfonate,narwedine-N-oxide, narwedine-N-oxide quinate and pseudonarwedine. It isnot intended that the present invention be limited by the type ofchemical substituent or substituents that is or are coordinated tonarwedine. Examples of chemical substituents include but are in no waylimited to hydrogen, methyl, ethyl, formyl, acetyl, phenyl, chloride,bromide, hydroxyl, methoxyl, ethoxyl, methylthiol, ethylthiol,propionyl, carboxyl, methoxy carbonyl, ethoxycarbonyl,methylthiocarbonyl, ethylthiocarbonyl, butylthiocarbonyl,dimethylcarbamyl, diethylcarbamyl, N-piperidinylcarbonyl,N-methyl-N-piperazinylcarbonyl, 2-(dimethylamino)ethylcarboxy,N-morpholinylcarbonyl, 2-(dimethylamino)ethylcarbamyl,1-piperidinylcarbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl,2-piperidinylethyl, 2-morpholinylethyl, 2-(dimethylamino)ethyl,2-(diethylamino)ethyl, butylthiol, dimethylamino, diethylamino,piperidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, N-methylpiperazinyland 2-(dimethylamino)ethylamino.

A “Suzuki reaction” refers to a chemical reaction between an aryl- orvinyl-boronic acid with an aryl- or vinyl halide that is catalyzed via apalladium complex as provided for in U.S. Pat. No. 6,136,157 toLindeberg et al., incorporated herein by reference. While not limitingthe scope of the present invention, the reaction is used to synthesizepoly-olefins, styrenes, substituted biphenyl complexes and incorporatealkyl halides including but in no way limited to alkyl bromides.

A “Henry aldol” reaction, also referred to as a “nitroaldol” reaction,is a reaction carried out between an aldehyde and nitromethane asprovided for in U.S. Pat. No. 7,312,191 to Rose et al., incorporatedherein by reference. The reaction results in the synthesis of aβ-hydroxy nitrosylated compound, also referred to as a nitroethylenecompound.

A “Grignard reagent” refers to chemical reagents which are prepared bythe reaction of magnesium metal with an organic halide. Gignard reagentsrefer to any of a class of reagents with the general formula RMgX, inwhich R is an organic radical, including but not limited to where R isan alkyl or aryl, and X is a halogen. Grignard reagents are used as asource of nucleophillic carbon. It is known that the preparation ofGrignard reagents are often quite difficult. Formation of these reagentsis inhibited by the presence of water and alcohols, ethers and halidesand by impurities on the surface of the magnesium turnings. While notlimiting the scope of the present invention, the reagent is commonlyused but not limited to reacting with acyl, epoxide, alcohols,heterocyclic, carboyxllic acids, esters, ethers, and otherelectrophillic atoms.

As used herein, “alkaloid” refers to a member of the class of naturallyoccurring chemical compounds containing basic nitrogen atoms. Alkaloidsare produced by a large variety of organisms, with many exhibitingpharmacological effects. While not limiting the scope of the presentinvention, alkaloids are often formulated as salts to enhance theirsolubility under physiological conditions. Examples of alkaloid saltcounter ions include the appropriate counter ion derived from but in noway limited to mineral acids such as hydrochloric acid and sulfuric acidas well as organic acid counter ions including but not limited totartaric acid and maleic acid.

“Epimers” refer to diastereomers that differ in configuration of onlyone stereogenic center. Diastereomers are a class of stereoisomers thatare non-superposable, non-mirror images of one another, unlikeenantiomers that are non-superposable mirror images of one another.

The term “salts”, as used herein, refers to any salt that complexes withidentified compounds contained herein while retaining a desiredfunction, e.g., biological activity. Examples of such salts include, butare not limited to, acid addition salts formed with inorganic acids(e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid, nitric acid, and the like), and salts formed with organic acidssuch as, but not limited to, acetic acid, oxalic acid, tartaric acid,succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid,benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic,acid, naphthalene sulfonic acid, naphthalene disulfonic acid, andpolygalacturonic acid.

As used herein, “hydrogen” means —H; “hydroxy” means —OH; “oxo” means═O; “halo” means independently —F, —Cl, —Br or —I; “amino” means —NH₂(see below for definitions of groups containing the term amino, e.g.,alkylamino); “hydroxyamino” means —NHOH; “nitro” means —NO₂; imino means═NH (see below for definitions of groups containing the term imino,e.g., alkylamino); “cyano” means —CN; “azido” means —N₃; “mercapto”means —SH; “thio” means ═S; “sulfonamido” means —NHS(O)₂—(see below fordefinitions of groups containing the term sulfonamido, e.g.,alkylsulfonamido); “sulfonyl” means —S(O)₂— (see below for definitionsof groups containing the term sulfonyl, e.g., alkylsulfonyl); and“silyl” means —SiH₃ (see below for definitions of group(s) containingthe term silyl, e.g., alkylsilyl).

For the groups below, the following parenthetical subscripts furtherdefine the groups as follows: “(Cn)” defines the exact number (n) ofcarbon atoms in the group; “(C≦n)” defines the maximum number (n) ofcarbon atoms that can be in the group; (Cn-n) defines both the minimum(n) and maximum number (n′) of carbon atoms in the group. For example,“alkoxy_((C≦10))” designates those alkoxy groups having from 1 to 10carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or any rangederivable therein (e.g., 3-10 carbon atoms)). Similarly,“alkyl_((C2-10))” designates those alkyl groups having from 2 to 10carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, or any rangederivable therein (e.g., 3-10 carbon atoms)).

The term “alkyl” when used without the “substituted” modifier refers toa non-aromatic monovalent group with a saturated carbon atom as thepoint of attachment, a linear or branched, cyclo, cyclic or acyclicstructure, no carbon-carbon double or triple bonds, and no atoms otherthan carbon and hydrogen. The groups, —CH₃ (Me), —CH₂CH₃ (Et),—CH₂CH₂CH₃ (n-Pr), —CH(CH₃)₂ (iso-Pr), —CH(CH₂)₂ (cyclopropyl),—CH₂CH₂CH₂CH₃ (n-Bu), —CH(CH₃)CH₂CH₃ (sec-butyl), —CH₂CH(CH₃)₂(iso-butyl), —C(CH₃)₃ (tert-butyl), —CH₂C(CH₃)₃ (neo-pentyl),cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexylmethyl arenon-limiting examples of alkyl groups. The term “substituted alkyl”refers to a non-aromatic monovalent group with a saturated carbon atomas the point of attachment, a linear or branched, cyclo, cyclic oracyclic structure, no carbon-carbon double or triple bonds, and at leastone atom independently selected from the group consisting of N, O, F,Cl, Br, I, Si, P, and S. The following groups are non-limiting examplesof substituted alkyl groups: —CH₂OH, —CH₂Cl, —CH₂Br, —CH₂SH, —CF₃,—CH₂CN, —CH₂C(O)H, —CH₂C(O)OH, —CH₂C(O)OCH₃, —CH₂C(O)NH₂, —CH₂C(O)NHCH₃,CH₂C(O)CH₃, —CH₂OCH₃, CH₂OCH₂CF₃, —CH₂OC(O)CH₃, —CH₂NH₂, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CH₂CH₂Cl, —CH₂CH₂OH, —CH₂CF₃—CH₂CH₂O(C)CH₃,—CH₂CH₂NHCO₂C(CH₃)₃, and —CH₂Si(CH₃)₃.

The term “alkanediyl” when used without the “substituted” modifierrefers to a non-aromatic divalent group, wherein the alkanediyl group isattached with two σ-bonds, with one or two saturated carbon atom(s) asthe point(s) of attachment, a linear or branched, cyclo, cyclic oracyclic structure, no carbon-carbon double or triple bonds, and no atomsother than carbon and hydrogen. The groups, —CH₂— (methylene), —CH₂CH₂—,

—CH₂C(CH₃)₂CH₂—, —CH₂CH₂CH₂—, and

are non-limiting examples of alkanediyl groups. The term “substitutedalkanediyl” refers to a non-aromatic monovalent group, wherein thealkynediyl group is attached with two σ-bonds, with one or two saturatedcarbon atom(s) as the point(s) of attachment, a linear or branched,cyclo, cyclic or acyclic structure, no carbon-carbon double or triplebonds, and at least one atom independently selected from the groupconsisting of N, O, F, Cl, Br, I, Si, P, and S. The following groups arenon-limiting examples of substituted alkanediyl groups: —CH(F)—, —CF₂—,—CH(Cl)—, —CH(OH)—, —CH(OCH₃)—, and —CH₂CH(Cl)—.

The term “alkenyl” when used without the “substituted” modifier refersto a monovalent group with a nonaromatic carbon atom as the point ofattachment, a linear or branched, cyclo, cyclic or acyclic structure, atleast one nonaromatic carbon-carbon double bond, no carbon-carbon triplebonds, and no atoms other than carbon and hydrogen. Non-limitingexamples of alkenyl groups include: —CH═CH₂ (vinyl), —CH═CHCH₃,—CH═CHCH₂CH₃, —CH₂CH═CH₂ (allyl), —CH₂CH═CHCH₃, and —CH═CH—C₆H₅. Theterm “substituted alkenyl” refers to a monovalent group with anonaromatic carbon atom as the point of attachment, at least onenonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, alinear or branched, cyclo, cyclic or acyclic structure, and at least oneatom independently selected from the group consisting of N, O, F, Cl,Br, I, Si, P, and S. The groups, —CH═CHF, —CH═CHCl and —CH═CHBr, arenon-limiting examples of substituted alkenyl groups.

The term “alkenediyl” when used without the “substituted” modifierrefers to a non-aromatic divalent group, wherein the alkenediyl group isattached with two σ-bonds, with two carbon atoms as points ofattachment, a linear or branched, cyclo, cyclic or acyclic structure, atleast one nonaromatic carbon-carbon double bond, no carbon-carbon triplebonds, and no atoms other than carbon and hydrogen. The groups, —CH═CH—,—CH═C(CH₃)CH₂—, —CH═CHCH₂—, and

are non-limiting examples of alkenediyl groups. The term “substitutedalkenediyl” refers to a non-aromatic divalent group, wherein thealkenediyl group is attached with two σ-bonds, with two carbon atoms aspoints of attachment, a linear or branched, cyclo, cyclic or acyclicstructure, at least one nonaromatic carbon-carbon double bond, nocarbon-carbon triple bonds, and at least one atom independently selectedfrom the group consisting of N, O, F, Cl, Br, I, Si, P, and S. Thefollowing groups are non-limiting examples of substituted alkenediylgroups: —CF═CH—, —C(OH)═CH—, and —CH₂CH═C(Cl)—.

The term “alkynyl” when used without the “substituted” modifier refersto a monovalent group with a nonaromatic carbon atom as the point ofattachment, a linear or branched, cyclo, cyclic or acyclic structure, atleast one carbon-carbon triple bond, and no atoms other than carbon andhydrogen. The groups, —C≡CH, —C≡CCH₃, —C≡CC₆H₅ and —CH₂C≡CCH₃, arenon-limiting examples of alkynyl groups. The term “substituted alkynyl”refers to a monovalent group with a nonaromatic carbon atom as the pointof attachment and at least one carbon-carbon triple bond, a linear orbranched, cyclo, cyclic or acyclic structure, and at least one atomindependently selected from the group consisting of N, O, F, Cl, Br, I,Si, P, and S. The group, —C≡CSi(CH₃)₃, is a non-limiting example of asubstituted alkynyl group.

The term “alkynediyl” when used without the “substituted” modifierrefers to a non-aromatic divalent group, wherein the alkynediyl group isattached with two σ-bonds, with two carbon atoms as points ofattachment, a linear or branched, cyclo, cyclic or acyclic structure, atleast one carbon-carbon triple bond, and no atoms other than carbon andhydrogen. The groups, —C≡C—, —C≡CCH₂—, and —C≡CCH(CH₃)— are non-limitingexamples of alkynediyl groups. The term “substituted alkynediyl” refersto a non-aromatic divalent group, wherein the alkynediyl group isattached with two σ-bonds, with two carbon atoms as points ofattachment, a linear or branched, cyclo, cyclic or acyclic structure, atleast one carbon-carbon triple bond, and at least one atom independentlyselected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.The groups —C≡CCFH— and —C≡CHCH(Cl)— are non-limiting examples ofsubstituted alkynediyl groups.

The term “aryl” when used without the “substituted” modifier refers to amonovalent group with an aromatic carbon atom as the point ofattachment, said carbon atom forming part of a six-membered aromaticring structure wherein the ring atoms are all carbon, and wherein themonovalent group consists of no atoms other than carbon and hydrogen.Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl,(dimethyl)phenyl, —C₆H₄CH₂CH₃ (ethylphenyl), —C₆H₄CH₂CH₂CH₃(propylphenyl), —C₆H₄CH(CH₃)₂, —C₆H₄CH(CH₂)₂, —C₆H₃(CH₃)CH₂CH₃(methylethylphenyl), —C₆H₄CH═CH₂ (vinylphenyl), —C₆H₄CH═CHCH₃,—C₆H₄C≡CH, —C₆H₄C≡CCH₃, naphthyl, and the monovalent group derived frombiphenyl. The term “substituted aryl” refers to a monovalent group withan aromatic carbon atom as the point of attachment, said carbon atomforming part of a six-membered aromatic ring structure wherein the ringatoms are all carbon, and wherein the monovalent group further has atleast one atom independently selected from the group consisting of N, O,F, Cl, Br, I, Si, P, and S, Non-limiting examples of substituted arylgroups include the groups: —C₆H₄F, —C₆H₄Cl, —C₆H₄Br, —C₆H₄I, —C₆H₄OH,—C₆H₄OCH₃, —C₆H₄OCH₂CH₃, —C₆H₄F, —C₆H₄OC(O)CH₃, —C₆H₄NH₂, —C₆H₄NHCH₃,—C₆H₄N(CH₃)₂, —C₆H₄CH₂OH, —C₆H₄CH₂OC(O) CH₃, —C₆H₄CH₂NH₂, —C₆H₄CF₃,—C₆H₄CN, —C₆H₄CHO, C₆H₄CHO, C₆H₄C(O) CH₃, —C₆H₄C(O)C₆H₅, —C₆H₄CO₂H,—C₆H₄CO₂CH₃, —C₆H₄CONH₂, —C₆H₄CONHCH₃, and —C₆H₄CON(CH₃)₂.

The term “arenediyl” when used without the “substituted” modifier refersto a divalent group, wherein the arenediyl group is attached with twoσ-bonds, with two aromatic carbon atoms as points of attachment, saidcarbon atoms forming part of one or more six-membered aromatic ringstructure(s) wherein the ring atoms are all carbon, and wherein themonovalent group consists of no atoms other than carbon and hydrogen.Non-limiting examples of arenediyl groups include:

The term “substituted arenediyl” refers to a divalent group, wherein thearenediyl group is attached with two σ-bonds, with two aromatic carbonatoms as points of attachment, said carbon atoms forming part of one ormore six-membered aromatic rings structure(s), wherein the ring atomsare all carbon, and wherein the divalent group further has at least oneatom independently selected from the group consisting of N, O, F, Cl,Br, I, Si, P, and S.

The term “aralkyl” when used without the “substituted” modifier refersto the monovalent group-alkanediyl-aryl, in which the terms alkanediyland aryl are each used in a manner consistent with the definitionsprovided above. Non-limiting examples of aralkyls are: phenylmethyl(benzyl, Bn), 1-phenyl-ethyl, 2-phenyl-ethyl, indenyl and2,3-dihydro-indenyl, provided that indenyl and 2,3-dihydro-indenyl areonly examples of aralkyl in so far as the point of attachment in eachcase is one of the saturated carbon atoms. When the term “aralkyl” isused with the “substituted” modifier, either one or both the alkanediyland the aryl is substituted. Non-limiting examples of substitutedaralkyls are: (3-chlorophenyl)-methyl, 2-oxo-2-phenyl-ethyl(phenylcarbonylmethyl), 2-chloro-2-phenyl-ethyl, chromanyl where thepoint of attachment is one of the saturated carbon atoms, andtetrahydroquinolinyl where the point of attachment is one of thesaturated atoms.

The term “heteroaryl” when used without the “substituted” modifierrefers to a monovalent group with an aromatic carbon atom or nitrogenatom as the point of attachment, said carbon atom or nitrogen atomforming part of an aromatic ring structure wherein at least one of thering atoms is nitrogen, oxygen or sulfur, and wherein the monovalentgroup consists of no atoms other than carbon, hydrogen, aromaticnitrogen, aromatic oxygen and aromatic sulfur. Non-limiting examples ofaryl groups include acridinyl, furanyl, imidazoimidazolyl,imidazopyrazolyl, imidazopyridinyl, imidazopyrimidinyl, indolyl,indazolinyl, methylpyridyl, oxazolyl, phenylimidazolyl, pyrrolyl,pyrimidyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl,tetrahydroquinolinyl, thienyl, triazinyl, pyrrolopyridinyl,pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolotriazinyl,pyrroloimidazolyl, chromenyl (where the point of attachment is one ofthe aromatic atoms), and chromanyl (where the point of attachment is oneof the aromatic atoms). The term “substituted heteroaryl” refers to amonovalent group with an aromatic carbon atom or nitrogen atom as thepoint of attachment, said carbon atom or nitrogen atom forming part ofan aromatic ring structure wherein at least one of the ring atoms isnitrogen, oxygen or sulfur, and wherein the monovalent group further hasat least one atom independently selected from the group consisting ofnon-aromatic nitrogen, non-aromatic oxygen, non aromatic sulfur F, Cl,Br, I, Si, and P.

The term “heteroarenediyl” when used without the “substituted” modifierrefers to a divalent group, wherein the heteroarenediyl group isattached with two σ-bonds, with an aromatic carbon atom or nitrogen atomas the point of attachment, said carbon atom or nitrogen atom twoaromatic atoms as points of attachment, said carbon atoms forming partof one or more six-membered aromatic ring structure(s) wherein the ringatoms are all carbon, and wherein the monovalent group consists of noatoms other than carbon and hydrogen. Non-limiting examples ofheteroarenediyl groups include:

The term “substituted heteroarenediyl” refers to a divalent group,wherein the heteroarenediyl group is attached with two σ-bonds, with twoaromatic carbon atoms as points of attachment, said carbon atoms formingpart of one or more six-membered aromatic rings structure(s), whereinthe ring atoms are all carbon, and wherein the divalent group furtherhas at least one atom independently selected from the group consistingof N, O, F, Cl, Br, I, Si, P, and S.

The term “heteroaralkyl” when used without the “substituted” modifierrefers to the monovalent group -alkanediyl-heteroaryl, in which theterms alkanediyl and heteroaryl are each used in a manner consistentwith the definitions provided above. Non-limiting examples of aralkylsare: pyridylmethyl, and thienylmethyl. When the term “heteroaralkyl” isused with the “substituted” modifier, either one or both the alkanediyland the heteroaryl is substituted.

The term “acyl” when used without the “substituted” modifier refers to amonovalent group with a carbon atom of a carbonyl group as the point ofattachment, further having a linear or branched, cyclo, cyclic oracyclic structure, further having no additional atoms that are notcarbon or hydrogen, beyond the oxygen atom of the carbonyl group. Thegroups, —CHO, —C(O)CH₃, —C(O)CH₂CH₃, —C(O)CH₂CH₂CH₃, —C(O)CH(CH₃)₂,—C(O)CH(CH₂)₂, —C(O)C₆H₅, —C(O)C₆H₄CH₃, —C(O)C₆H₄CH₂CH₃, —COC₆H₃(CH₃)₂,and —C(O)CH₂C₆H₅, are non-limiting examples of acyl groups. The term“acyl” therefore encompasses, but is not limited to groups sometimesreferred to as “alkyl carbonyl” and “aryl carbonyl” groups. The term“substituted acyl” refers to a monovalent group with a carbon atom of acarbonyl group as the point of attachment, further having a linear orbranched, cyclo, cyclic or acyclic structure, further having at leastone atom, in addition to the oxygen of the carbonyl group, independentlyselected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.The groups, —C(O)CH₂CF₃, —CO₂H (carboxyl), —CO₂CH₃ (methylcarboxyl),—CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, —CO₂C₆H₅, —CO₂CH(CH₃)₂, —CO₂CH(CH₂)₂,—C(O)NH₂ (carbamoyl), —C(O)NHCH₃, —C(O)NHCH₂CH₃, —CONHCH(CH₃)₂,—CONHCH(CH₂)₂, —CON(CH₃)₂, —CONHCH₂CF₃, —CO-pyridyl, —CO-imidazoyl, and—C(O)N₃, are non-limiting examples of substituted acyl groups. The term“substituted acyl” encompasses, but is not limited to, “heteroarylcarbonyl” groups.

The term “alkylidene” when used without the “substituted” modifierrefers to the divalent group ═CRR′, wherein the alkylidene group isattached with one σ-bond and one π-bond, in which R and R′ areindependently hydrogen, alkyl, or R and R′ are taken together torepresent alkanediyl. Non-limiting examples of alkylidene groupsinclude: ═CH₂, ═CH(CH₂CH₃), and ═C(CH₃)₂. The term “substitutedalkylidene” refers to the group ═CRR′, wherein the alkylidene group isattached with one σ-bond and one π-bond, in which R and R′ areindependently hydrogen, alkyl, substituted alkyl, or R and R′ are takentogether to represent a substituted alkanediyl, provided that either oneof R and R′ is a substituted alkyl or R and R′ are taken together torepresent a substituted alkanediyl.

The term “alkoxy” when used without the “substituted” modifier refers tothe group —OR, in which R is an alkyl, as that term is defined above.Non-limiting examples of alkoxy groups include: —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, —OCH(CH₃)₂, —OCH(CH₂)₂, —O-cyclopentyl, and —O-cyclohexyl.The term “substituted alkoxy” refers to the group —OR, in which R is asubstituted alkyl, as that term is defined above. For example, —OCH₂CF₃is a substituted alkoxy group.

Similarly, the terms “alkenyloxy”, “alkynyloxy”, “aryloxy”, “aralkoxy”,“heteroaryloxy”, “heteroaralkoxy” and “acyloxy”, when used without the“substituted” modifier, refers to groups, defined as —OR, in which R isalkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and acyl,respectively, as those terms are defined above. When any of the termsalkenyloxy, alkynyloxy, aryloxy, aralkyloxy and acyloxy is modified by“substituted,” it refers to the group —OR, in which R is substitutedalkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and acyl,respectively.

The term “alkylamino” when used without the “substituted” modifierrefers to the group —NHR, in which R is an alkyl, as that term isdefined above. Non-limiting examples of alkylamino groups include:—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —NHCH(CH₂)₂,—NHCH₂CH₂CH₂CH₃, —NHCH(CH₃)CH₂CH₃, —NHCH₂CH(CH₃)₂, —NHC(CH₃)₃,—NH-cyclopentyl, and —NH-cyclohexyl. The term “substituted alkylamino”refers to the group —NHR, in which R is a substituted alkyl, as thatterm is defined above. For example, —NHCH₂CF₃ is a substitutedalkylamino group.

The term “dialkylamino” when used without the “substituted” modifierrefers to the group —NRR′, in which R and R′ can be the same ordifferent alkyl groups, or R and R′ can be taken together to representan alkanediyl having two or more saturated carbon atoms, at least two ofwhich are attached to the nitrogen atom. Non-limiting examples ofdialkylamino groups include: —NHC(CH₃)₃, —N(CH₃)CH₂CH₃, —N(CH₂CH₃)₂,N-pyrrolidinyl, and N-piperidinyl. The term “substituted dialkylamino”refers to the group —NRR′, in which R and R′ can be the same ordifferent substituted alkyl groups, one of R or R′ is an alkyl and theother is a substituted alkyl, or R and R′ can be taken together torepresent a substituted alkanediyl with two or more saturated carbonatoms, at least two of which are attached to the nitrogen atom.

The terms “alkoxyamino”, “alkenylamino”, “alkynylamino”, “arylamino”,“aralkylamino”, “heteroarylamino”, “heteroaralkylamino”, and“alkylsulfonylamino” when used without the “substituted” modifier,refers to groups, defined as —NHR, in which R is alkoxy, alkenyl,alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and alkylsulfonyl,respectively, as those terms are defined above. A non-limiting exampleof an arylamino group is —NHC₆H₅. When any of the terms alkoxyamino,alkenylamino, alkynylamino, arylamino, aralkylamino, heteroarylamino,heteroaralkylamino and alkylsulfonylamino is modified by “substituted,”it refers to the group —NHR, in which R is substituted alkoxy, alkenyl,alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and alkylsulfonyl,respectively.

The term “amido” (acylamino), when used without the “substituted”modifier, refers to the group —NHR, in which R is acyl, as that term isdefined above. A non-limiting example of an acylamino group is—NHC(O)CH₃. When the term amido is used with the “substituted” modifier,it refers to groups, defined as —NHR, in which R is substituted acyl, asthat term is defined above. The groups —NHC(O)OCH₃ and —NHC(O)NHCH₃ arenon-limiting examples of substituted amido groups.

The term “alkylimino” when used without the “substituted” modifierrefers to the group ═NR, wherein the alkylimino group is attached withone σ-bond and one π-bond, in which R is an alkyl, as that term isdefined above. Non-limiting examples of alkylimino groups include:═NCH₃, ═NCH₂CH₃ and ═N-cyclohexyl. The term “substituted alkylimino”refers to the group ═NR, wherein the alkylimino group is attached withone σ-bond and one π-bond, in which R is a substituted alkyl, as thatterm is defined above. For example, ═NCH₂CF₃ is a substituted alkyliminogroup.

Similarly, the terms “alkenylimino”, “alkynylimino”, “arylimino”,“aralkylimino”, “heteroarylimino”, “heteroaralkylimino” and “acylimino”,when used without the “substituted” modifier, refers to groups, definedas ═NR, wherein the alkylimino group is attached with one σ-bond and oneπ-bond, in which R is alkenyl, alkynyl, aryl, aralkyl, heteroaryl,heteroaralkyl and acyl, respectively, as those terms are defined above.When any of the terms alkenylimino, alkynylimino, arylimino,aralkylimino and acylimino is modified by “substituted,” it refers tothe group ═NR, wherein the alkylimino group is attached with one σ-bondand one π-bond, in which R is substituted alkenyl, alkynyl, aryl,aralkyl, heteroaryl, heteroaralkyl and acyl, respectively.

The term “alkylthio” when used without the “substituted” modifier refersto the group —SR, in which R is an alkyl, as that term is defined above.Non-limiting examples of alkylthio groups include: —SCH₃, —SCH₂CH₃,—SCH₂CH₂CH₃, —SCH(CH₃)₂, —SCH(CH₂)₂, —S-cyclopentyl, and —S-cyclohexyl.The term “substituted alkylthio” refers to the group —SR, in which R isa substituted alkyl, as that term is defined above. For example,—SCH₂CF₃ is a substituted alkylthio group.

Similarly, the terms “alkenylthio”, “alkynylthio”, “arylthio”,“aralkylthio”, “heteroarylthio”, “heteroaralkylthio”, and “acylthio”,when used without the “substituted” modifier, refers to groups, definedas —SR, in which R is alkenyl, alkynyl, aryl, aralkyl, heteroaryl,heteroaralkyl and acyl, respectively, as those terms are defined above.When any of the terms alkenylthio, alkynylthio, arylthio, aralkylthio,heteroarylthio, heteroaralkylthio, and acylthio is modified by“substituted,” it refers to the group —SR, in which R is substitutedalkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and acyl,respectively.

The term “thioacyl” when used without the “substituted” modifier refersto a monovalent group with a carbon atom of a thiocarbonyl group as thepoint of attachment, further having a linear or branched, cyclo, cyclicor acyclic structure, further having no additional atoms that are notcarbon or hydrogen, beyond the sulfur atom of the carbonyl group. Thegroups, —CHS, —C(S)CH₃, —C(S)CH₂CH₃, —C(S)CH₂CH₂CH₃, —C(S)CH(CH₃)₂,—C(S)CH(CH₂)₂, —C(S)C₆H₅, —C(S)C₆H₄CH₃, —C(S)C₆H₄CH₂CH₃,—C(S)C₆H₃(CH₃)₂, and —C(S)CH₂C₆H₅, are non-limiting examples of thioacylgroups. The term “thioacyl” therefore encompasses, but is not limitedto, groups sometimes referred to as “alkyl thiocarbonyl” and “arylthiocarbonyl” groups. The term “substituted thioacyl” refers to aradical with a carbon atom as the point of attachment, the carbon atombeing part of a thiocarbonyl group, further having a linear or branched,cyclo, cyclic or acyclic structure, further having at least one atom, inaddition to the sulfur atom of the carbonyl group, independentlyselected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.The groups, —C(S)CH₂CF₃, —C(S)O₂H, —C(S)OCH₃, —C(S)OCH₂CH₃,—C(S)OCH₂CH₂CH₃, —C(S)OC₆H₅, —C(S)OCH(CH₃)₂, —C(S)OCH(CH₂)₂, —C(S)NH₂,and —C(S)NHCH₃, are non-limiting examples of substituted thioacylgroups. The term “substituted thioacyl” encompasses, but is not limitedto, “heteroaryl thiocarbonyl” groups.

The term “alkylsulfonyl” when used without the “substituted” modifierrefers to the group —S(O)₂R, in which R is an alkyl, as that term isdefined above. Non-limiting examples of alkylsulfonyl groups include:—S(O)₂CH₃, —S(O)₂CH₂CH₃, —S(O)₂CH₂CH₂CH₃, —S(O)₂CH(CH₃)₂, —S(O)₂CH(CH₂)₂, —S(O)₂-cyclopentyl, and —S(O)₂-cyclohexyl. The term“substituted alkylsulfonyl” refers to the group —S(O)₂R, in which R is asubstituted alkyl, as that term is defined above. For example,—S(O)₂CH₂CF₃ is a substituted alkylsulfonyl group.

Similarly, the terms “alkenylsulfonyl”, “alkynylsulfonyl”,“arylsulfonyl”, “aralkylsulfonyl”, “heteroarylsulfonyl”, and“heteroaralkylsulfonyl” when used without the “substituted” modifier,refers to groups, defined as —S(O)₂R, in which R is alkenyl, alkynyl,aryl, aralkyl, heteroaryl, and heteroaralkyl, respectively, as thoseterms are defined above. When any of the terms alkenylsulfonyl,alkynylsulfonyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfonyl, andheteroaralkylsulfonyl is modified by “substituted,” it refers to thegroup —S(O)₂R, in which R is substituted alkenyl, alkynyl, aryl,aralkyl, heteroaryl and heteroaralkyl, respectively.

The term “alkylammonium” when used without the “substituted” modifierrefers to a group, defined as —NH₂R⁺, —NHRR′⁺, or —NRR′R″⁺, in which R,R′ and R″ are the same or different alkyl groups, or any combination oftwo of R, R′ and R″ can be taken together to represent an alkanediyl.Non-limiting examples of alkylammonium cation groups include:—NH₂(CH₃)⁺, —NH₂(CH₂CH₃)⁺, —NH₂(CH₂CH₂CH₃)+, —NH(CH₃)₂ ⁺, —NH(CH₂CH₃)₂⁺, —NH(CH₂CH₂CH₃)₂ ⁺, —N(CH₃)₃ ⁺, —N(CH₃)(CH₂CH₃)₂ ⁺, —N(CH₃)₂(CH₂CH₃)⁺,—NH₂C(CH₃)₃ ⁺, —NH(cyclopentyl)₂ ⁺, and —NH₂(cyclohexyl)⁺. The term“substituted alkylammonium” refers —NH₂R⁺, —NHRR′⁺, or —NRR′R″⁺, inwhich at least one of R, R′ and R″ is a substituted alkyl or two of R,R′ and R″ can be taken together to represent a substituted alkanediyl.When more than one of R, R′ and R″ is a substituted alkyl, they can bethe same of different. Any of R, R′ and R″ that are not eithersubstituted alkyl or substituted alkanediyl, can be either alkyl, eitherthe same or different, or can be taken together to represent aalkanediyl with two or more carbon atoms, at least two of which areattached to the nitrogen atom shown in the formula. The term“alkylsulfonium” when used without the “substituted” modifier refers tothe group —SRR′⁺, in which R and R′ can be the same or different alkylgroups, or R and R′ can be taken together to represent an alkanediyl.Non-limiting examples of alkylsulfonium groups include: —SH(CH₃)⁺,—SH(CH₂CH₃)⁺, —SH(CH₂CH₂CH₃)⁺, —S(CH₃)₂ ⁺, —S(CH₂CH₃)₂ ⁺, —S(CH₂CH₂CH₃)₂⁺, —SH(cyclopentyl)⁺, and —SH(cyclohexyl)⁺. The term “substitutedalkylsulfonium” refers to the group —SRR′⁺, in which R and R′ can be thesame or different substituted alkyl groups, one of R′ or R′ is an alkyland the other is a substituted alkyl, or R and R′ can be taken togetherto represent a substituted alkanediyl. For example, —SH(CH₂CF₃)⁺ is asubstituted alkylsulfonium group.

The term “alkylsilyl” when used without the “substituted” modifierrefers to a monovalent group, defined as —SiH₂R, —SiHRR′, or —SiRR′R″,in which R, R′ and R″ can be the same or different alkyl groups, or anycombination of two of R, R′ and R″ can be taken together to represent analkanediyl. The groups, —SiH₂CH₃, —SiH(CH₃)₂, —Si(CH₃)₃ and—Si(CH₃)₂C(CH₃)₃, are non-limiting examples of unsubstituted alkylsilylgroups. The term “substituted alkylsilyl” refers —SiH₂R, —SiHRR′, or—SiRR′R″, in which at least one of R, R′ and R″ is a substituted alkylor two of R, R′ and R″ can be taken together to represent a substitutedalkanediyl. When more than one of R, R′ and R″ is a substituted alkyl,they can be the same of different. Any of R, R′ and R″ that are noteither substituted alkyl or substituted alkanediyl, can be either alkyl,either the same or different, or can be taken together to represent aalkanediyl with two or more saturated carbon atoms, at least two ofwhich are attached to the silicon atom.

In addition, atoms making up the compounds of the present invention areintended to include all isotopic forms of such atoms. Isotopes, as usedherein, include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium, and isotopes of carboninclude ¹³C and ¹⁴C. Similarly, it is contemplated that one or morecarbon atom(s) of a compound of the present invention may be replaced bya silicon atom(s). Furthermore, it is contemplated that one or moreoxygen atom(s) of a compound of the present invention may be replaced bya sulfur or selenium atom(s).

A compound having a formula that is represented with a dashed bond isintended to include the formulae optionally having zero, one or moredouble bonds. Thus, for example, the structure

includes the structures

As will be understood by a person of skill in the art, no one such ringatom forms part of more than one double bond.

Any undefined valency on an atom of a structure shown in thisapplication implicitly represents a hydrogen atom bonded to the atom.

A ring structure shown with an unconnected “R” group, indicates that anyimplicit hydrogen atom on that ring can be replaced with that R group.In the case of a divalent R group (e.g., oxo, imino, thio, alkylidene,etc.), any pair of implicit hydrogen atoms attached to one atom of thatring can be replaced by that R group. This concept is as exemplifiedbelow:

-   -   represents

As used herein, a “chiral auxiliary” refers to a removable chiral groupthat is capable of influencing the stereoselectivity of a reaction.Persons of skill in the art are familiar with such compounds, and manyare commercially available.

The term “protecting group,” as that term is used in the specificationand/or claims, is used in the conventional chemical sense as a group,which reversibly renders unreactive a functional group under certainconditions of a desired reaction and is understood not to be H. Afterthe desired reaction, protecting groups may be removed to deprotect theprotected functional group. All protecting groups should be removable(and hence, labile) under conditions which do not degrade a substantialproportion of the molecules being synthesized. In contrast to aprotecting group, a “capping group” permanently binds to a segment of amolecule to prevent any further chemical transformation of that segment.It should be noted that the functionality protected by the protectinggroup may or may not be a part of what is referred to as the protectinggroup.

Protecting groups include but are not limited to: Alcohol protectinggroups: Acetoxy group, β-Methoxyethoxymethyl ether (MEM), methoxymethylether (MOM), p-methoxybenzyl ether (PMB), methylthiomethyl ether,pivaloyl (Piv), tetrahydropyran (THP), silyl ethers (including but notlimited to trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), andtriisopropylsilyl (TIPS) ethers), methyl ethers, and ethoxyethyl ethers(EE). Amine protecting groups: carbobenzyloxy (Cbz) group,p-methoxybenzyl carbonyl (Moz or MeOZ) group, tert-butyloxycarbonyl(BOC) group, 9-fluorenylmethyloxycarbonyl (FMOC) group, benzyl (Bn)group, p-methoxybenzyl (PMB), dimethoxybenzyl (DMPM), p-methoxyphenyl(PMP) group, tosyl (Ts) group, and other sulfonamides (Nosyl & Nps)groups. Carbonyl protecting groups: acetals, ketals, acylals, anddithianes. Carboxylic acid protecting groups: alkyl esters, aryl esters,silyl esters. Protection of terminal alkynes protected as propargylalcohols in the Favorskii reaction.

The term “leaving group,” as that term is used in the specificationand/or claims, is an atom or group (charged or uncharged) that becomesdetached from an atom in what is considered to be the residual or mainpart of the substrate in a specified reaction.

Leaving groups include, but are not limited to: NH₂ ⁻ (amine), CH₃O⁻(methoxy), HO⁻ (hydroxyl), CH₃COO⁻ (carboxylate), H₂O (water), F⁻, Cl⁻,Br⁻, I⁻, N₃ ⁻ (azide), SCN⁻ (thiocyanate), NO₂ (nitro), and protectinggroups.

The use of the word “a” or “an,” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.”

Throughout this application, the term “about” is used to indicate that avalue includes the inherent variation of error for the device, themethod being employed to determine the value, or the variation thatexists among the study subjects.

The terms “comprise,” “have” and “include” are open-ended linking verbs.Any forms or tenses of one or more of these verbs, such as “comprises,”“comprising,” “has,” “having,” “includes” and “including,” are alsoopen-ended. For example, any method that “comprises,” “has” or“includes” one or more steps is not limited to possessing only those oneor more steps and also covers other unlisted steps.

The term “effective,” as that term is used in the specification and/orclaims, means adequate to accomplish a desired, expected, or intendedresult.

The term “hydrate” when used as a modifier to a compound means that thecompound has less than one (e.g., hemihydrate), one (e.g., monohydrate),or more than one (e.g., dihydrate) water molecules associated with eachcompound molecule, such as in solid forms of the compound.

As used herein, the term “IC₅₀” refers to an inhibitory dose which is50% of the maximum response obtained.

An “isomer” of a first compound is a separate compound in which eachmolecule contains the same constituent atoms as the first compound, butwhere the configuration of those atoms in three dimensions differs.

As used herein, the term “patient” or “subject” refers to a livingmammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat,mouse, rat, guinea pig, or transgenic species thereof. In certainembodiments, the patient or subject is a primate. Non-limiting examplesof human subjects are adults, juveniles, infants and fetuses.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,2-naphthalenesulfonic acid, 3-phenylpropionic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid,aliphatic mono- and dicarboxylicacids, aliphatic sulfuric acids,aromatic sulfuric acids, benzenesulfonic acid, benzoic acid,camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid,glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid,laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelicacid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoicacid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substitutedalkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid,salicylic acid, stearic acid, succinic acid, tartaric acid,tertiarybutylacetic acid, trimethylacetic acid, and the like.Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike. It should be recognized that the particular anion or cationforming a part of any salt of this invention is not critical, so long asthe salt, as a whole, is pharmacologically acceptable. Additionalexamples of pharmaceutically acceptable salts and their methods ofpreparation and use are presented in Handbook of Pharmaceutical SaltsProperties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag HelveticaChimica Acta, 2002),

As used herein, “predominantly one enantiomer” means that a compoundcontains at least about 85% of one enantiomer, or more preferably atleast about 90% of one enantiomer, or even more preferably at leastabout 95% of one enantiomer, or most preferably at least about 99% ofone enantiomer. Similarly, the phrase “substantially free from otheroptical isomers” means that the composition contains at most about 15%of another enantiomer or diastereomer, more preferably at most about 10%of another enantiomer or diastereomer, even more preferably at mostabout 5% of another enantiomer or diastereomer, and most preferably atmost about 1% of another enantiomer or diastereomer.

“Prevention” or “preventing” includes: (1) inhibiting the onset of adisease in a subject or patient which may be at risk and/or predisposedto the disease but does not yet experience or display any or all of thepathology or symptomatology of the disease, and/or (2) slowing the onsetof the pathology or symptomatology of a disease in a subject or patientwhich may be at risk and/or predisposed to the disease but does not yetexperience or display any or all of the pathology or symptomatology ofthe disease.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an inhibitor according to the present invention. The prodrug itselfmay or may not also have activity with respect to a given targetprotein. For example, a compound comprising a hydroxy group may beadministered as an ester that is converted by hydrolysis in vivo to thehydroxy compound. Suitable esters that may be converted in vivo intohydroxy compounds include acetates, citrates, lactates, phosphates,tartrates, malonates, oxalates, salicylates, propionates, succinates,fumarates, maleates, methylene-bis-β-hydroxynaphthoate, gentisates,isethionates, di-p-toluoyltartrates, methane-sulfonates,ethanesulfonates, benzenesulfonates, p-toluenesulfonates,cyclohexyl-sulfamates, quinates, esters of amino acids, and the like.Similarly, a compound comprising an amine group may be administered asan amide that is converted by hydrolysis in vivo to the amine compound.

The term “saturated” when referring to an atom means that the atom isconnected to other atoms only by means of single bonds.

A “stereoisomer” or “optical isomer” is an isomer of a given compound inwhich the same atoms are bonded to the same other atoms, but where theconfiguration of those atoms in three dimensions differs. “Enantiomers”are stereoisomers of a given compound that are mirror images of eachother, like left and right hands. “Diastereomers” are stereoisomers of agiven compound that are not enantiomers.

Enantiomers are compounds that individually have properties said to have“optical activity” and consist of chiral molecules. If a chiral moleculeis dextrorotary, its enantiomer will be levorotary, and vice-versa. Infact, the enantiomers will rotate polarized light the same number ofdegrees, but in opposite directions. “Dextrorotation” and “levorotation”(also spelled laevorotation) refer, respectively, to the properties ofrotating plane polarized light clockwise (for dextrorotation) orcounterclockwise (for levorotation). A compound with dextrorotation iscalled “dextrorotary,” while a compound with levorotation is called“levorotary”.

A standard measure of the degree to which a compound is dextrorotary orlevorotary is the quantity called the “specific rotation” “[α]”.Dextrorotary compounds have a positive specific rotation, whilelevorotary compounds have negative. Two enantiomers have equal andopposite specific rotations. A dextrorotary compound is prefixed “(+)-”or “d-”. Likewise, a levorotary compound is often prefixed “(−)-” or“l-”. These “d-” and “l-” prefixes should not be confused with the “D-”and “L-” prefixes based on the actual configuration of each enantiomer,with the version synthesized from naturally occurring (+)-compound beingconsidered the D-form. A mixture of enantiomers of the compounds isprefixed “(±)-”. An equal mixture of enantiomers of the compounds isconsidered “optically inactive”.

When used herein, unless otherwise specified, “morphine” refers to amixture of enantiomers of morphine, “(±)-morphine.” When used herein,unless otherwise specified, galanthamine refers to a mixture ofenantiomers of galanthamine, “(±) galanthamine,” or a single enantiomer,e.g. “(−)-galanthamine.”

Compounds 2, 14, 24, 25 and 26 are racemates, but the structures aredrawn in FIGS. 7 A & B (for clarity) as a single enantiomer with theirconfiguration corresponding to that of (−)-galanthamine.

The invention contemplates that for any stereocenter or axis ofchirality for which stereochemistry has not been defined, thatstereocenter or axis of chirality can be present in its R form, S form,or as a mixture of the R and S forms, including racemic and non-racemicmixtures.

“Substituent convertible to hydrogen in vivo” means any group that isconvertible to a hydrogen atom by enzymological or chemical meansincluding, but not limited to, hydrolysis and hydrogenolysis. Examplesinclude hydrolyzable groups, such as acyl groups, groups having anoxycarbonyl group, amino acid residues, peptide residues,o-nitrophenylsulfenyl, trimethylsilyl, tetrahydro-pyranyl,diphenylphosphinyl, and the like. Examples of acyl groups includeformyl, acetyl, trifluoroacetyl, and the like. Examples of groups havingan oxycarbonyl group include ethoxycarbonyl, tert-butoxycarbonyl(—C(O)OC(CH₃)₃), benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,vinyloxycarbonyl, β-(p-toluenesulfonyl)ethoxycarbonyl, and the like.

The present invention contemplates the above-described compositions in“therapeutically effective amounts” or “pharmaceutically effectiveamounts”, which means that amount which, when administered to a subjector patient for treating a disease, is sufficient to effect suchtreatment for the disease or to emeliorate one or more symptoms of adisease or condition (e.g. emeliorate pain).

The above definitions supersede any conflicting definition in any of thereference that is incorporated by reference herein.

The present invention contemplates, in certain embodiments inhibiting orpreventing disease (e.g. treating early Alzheimer's with galanthamine).As used herein, the terms “prevent” and “preventing” include theprevention of the recurrence, spread or onset of a disease or disorder.It is not intended that the present invention be limited to completeprevention. In some embodiments, the onset is delayed, or the severityof the disease or disorder is reduced. Studies with galanthamine haveshowed mild cognitive and global benefits for patients with Alzheimer'sdisease.

As used herein, the terms “treat” and “treating” are not limited to thecase where the subject (e.g. patient) is cured and the disease iseradicated. Rather, the present invention also contemplates treatmentthat merely reduces symptoms, improves (to some degree) and/or delaysdisease progression. It is not intended that the present invention belimited to instances wherein a disease or affliction is cured. It issufficient that symptoms are reduced.

“Subject” refers to any mammal, preferably a human patient, livestock,or domestic pet.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans. Theterm “carrier” refers to a diluent, adjuvant, excipient or vehicle withwhich the active compound is administered. Such pharmaceutical vehiclescan be liquids, such as water and oils, including those of petroleum,animal, vegetable or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil and the like. The pharmaceutical vehicles can besaline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, urea, and the like. In addition, auxiliary, stabilizing,thickening, lubricating and coloring agents can be used. Whenadministered to a subject, the pharmaceutically acceptable vehicles arepreferably sterile. Water can be the vehicle when the active compound isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid vehicles, particularlyfor injectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene glycol,water, ethanol and the like. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents, or pHbuffering agents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods for the synthesis of morphineand derivatives thereof. In preferred embodiments, the invention relatesto methods for improving the efficiency and overall yield of saidmorphine and derivatives. It is not intended that the present inventionbe limited to any particular chemical, biochemical or biologicalmechanism or theory.

In preferred embodiments, the invention relates to methods andcompositions comprising morphine and derivatives thereof. Morphine((5a,6a)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol; C₁₇H₁₉NO₃;MW=285.4), a member of the alkaloid class of compounds, is a highlyeffective analgesic used in a myriad of pharmaceutical and biomedicalapplications. While there are numerous reported synthetic strategies forobtaining limited quantities and percent yields of morphine alkaloidssuch as Zezula et al. (2007) Synlett, 2863-2867; Omori et al. (2007)Synlett, 2859-2862; Uchida et al. (2006) Org. Lett. 8, 5311-5313 andTrost et al. (2005) J. Am. Chem. Soc. 127, 14785-14803, all of which arehereby incorporated by reference, one of the most practical syntheticstrategies for obtaining opium alkaloids is the Rice adaptation of theGrewe strategy as provided for in Rice (1980) J. Org. Chem. 45,3135-3137, hereby incorporated by reference. While not limiting thescope of the current invention, the biosynthetic steps utilized bynature for the generation of morphine alkaloids is well understood. Asprovided for in FIG. 1, (R)-reticuline (1) is converted intosalutaridine (2) through an enzymatically mediated ortho-para phenolicoxidation as provided for in Barton et al. (1965) Journal of theChemical Society, 2423-2438, incorporated herein by reference.Salutaridine (2) is subsequently transformed in vivo into codienone 3(via thebaine), which is reduced to codeine (4) and demethylated to givemorphine (5).

The efficient phenolic oxidative pathway undertaken in plants to themost effective analgesics in all of medicinal practice underscores theneed to deduce the enzymatically-controlled pathway to these agents.However, attempts to mimic such aesthetic chemistry in the laboratoryfor the practical production of these important compounds in anefficient and economical manner, has not resulted in practical yields of(2) or related derivatives.

While not limiting the scope of the present invention to any particulartheory, one of the central issues in morphine and morphine derivativesynthesis is the construction of the cross-conjugated2,5-cyclohexadienone chromophore imbedded within salutaridine (2) in aneffective practical manner. Clearly, the published methods have beenoverwhelmingly influenced by the Barton phenolic oxidative biogeneticdogma as provided for in Studies in Natural Products Chemistry, Rahman,A, editor. Volume 18, Stereoselective Synthesis (Part K): A HistoricalPerspective of Morphine Syntheses, Hudlicky, T.; Butora, G.; Fearnley,S. P.; Gum, A. G.; Stabile, M. R. 1996, 43-154. Elsevier Publishers, NewYork; The Alkaloids, Cordell, G. A. and Brossi, A., editors. Volume 45,Chapter 2. “The Morphine Alkaloids,” Szántay, C.; Dörnyei, G.; Blaskó,G. 1994, 128-222. Academic Press, New York and Barton, D. H. R.; Kirby,G. W.; Steglich, W.; Thomas, G. M.; Battersby, A. R.; Dobson, T. A. andRamuz, H. (1965) Journal of the Chemical Society, 2423-2438, all ofwhich are hereby incorporated by reference. While phenolic oxidationprovides a structurally simplifying and unifying explanation of a largenumber of natural product structures, it has, at an experimental level,invariably resulted in low yields when applied to the in vitroconversion of phenols into cross-conjugated 2,5-cyclohexadienones. Whileintramolecular C-alkylation of phenols to form 2,5-cyclohexadienones hasbeen employed, and the applications of this non-oxidative methodology tothe synthesis of a wide range of both natural and unnatural products,this type of reaction has not been used for the synthesis of morphinans.It is known that intramolecular alkylation of phenolate anions canresult in O-alkylation (remains aromatic), versus C-alkylation of thephenolate anion that results in either 2,4- or 2,5-conjugatedcyclohexadienones. While not limiting the present invention to anyparticular theory or mechanism, applying the intramolecular phenolalkylation reaction (FIG. 2) to the synthesis of a suitably substitutedcross-conjugated 2,5-cyclohexadienone would require, in its simplestform, the conversion of (6) into (7). The acetal (C₁₋₆ carbon atom) in(7) will eventually evolve into the D-ring of morphine by a reductiveamination reaction.

In preferred embodiments, the invention relates to improved methods forthe synthesis of galanthamine and intermediates thereof. Galanthamine((4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef]-[2]-benzazepin-6-ol;C₁₇H₂₁NO₃; MW=287), an amaryllidaceae alkaloid, has found extensive usein the early treatment of Alzheimer's disease. The compound may beisolated via synthesis or from plants such as the Caucasian snowdrop(Voronov's snowdrop), Lycoris radiata (red spider lily) and Galanthusworonowii (Amaryllidaceae) and related species. While not limiting thepresent invention to any particular theory, it is believed that thecompound is metabolized primarily through the liver. The extraction ofgalanthamine from the bulbs of the aforementioned species does notsupply sufficient material for the on-going clinical evaluation andtreatment of early Alzheimer's patients. Commercially available suppliesof galanthamine are obtained via a laborious nine-step synthetic schemethat results in an overall yield of only 12.4% as provided for inKüenburg et al. (1999) Organic Process Research and Development 3,425-431, incorporated herein by reference. These difficulties inobtaining sufficient supplies of galanthamine underscore the need formore efficient synthetic strategies for obtaining the compound.

Pharmaceutical Formulations

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155, hereby incorporated byreference).

In a preferred embodiment, the active compound and optionally anothertherapeutic or prophylactic agent are formulated in accordance withroutine procedures as pharmaceutical compositions adapted forintravenous administration to human beings. Typically, the activecompounds for intravenous administration are solutions in sterileisotonic aqueous buffer. Where necessary, the compositions can alsoinclude a solubilizing agent. Compositions for intravenousadministration can optionally include a local anesthetic such aslignocaine to ease pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form, for example, as a dry lyophilized powder or water freeconcentrate in a hermetically sealed container such as an ampoule orsachette indicating the quantity of active agent. Where the activecompound is to be administered by infusion, it can be dispensed, forexample, with an infusion bottle containing sterile pharmaceutical gradewater or saline. Where the active compound is administered by injection,an ampoule of sterile water for injection or saline can be provided sothat the ingredients can be mixed prior to administration.

Compositions for oral delivery can be in the form of tablets, lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups, or elixirs, for example. Orally administered compositions cancontain one or more optional agents, for example, sweetening agents suchas fructose, aspartame or saccharin; flavoring agents such aspeppermint, oil of wintergreen, or cherry; coloring agents; andpreserving agents, to provide a pharmaceutically palatable preparation.Moreover, where in tablet or pill form, the compositions can be coatedto delay disintegration and absorption in the gastrointestinal tractthereby providing a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for an orally administered of theactive compound. In these later platforms, fluid from the environmentsurrounding the capsule is imbibed by the driving compound, which swellsto displace the agent or agent composition through an aperture. Thesedelivery platforms can provide an essentially zero order deliveryprofile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, and the like. Suchvehicles are preferably of pharmaceutical grade.

Further, the effect of the active compound can be delayed or prolongedby proper formulation. For example, a slowly soluble pellet of theactive compound can be prepared and incorporated in a tablet or capsule.The technique can be improved by making pellets of several differentdissolution rates and filling capsules with a mixture of the pellets.Tablets or capsules can be coated with a film that resists dissolutionfor a predictable period of time. Even the parenteral preparations canbe made long acting, by dissolving or suspending the compound in oily oremulsified vehicles, which allow it to disperse only slowly in theserum.

Compositions for use in accordance with the present invention can beformulated in conventional manner using one or more physiologicallyacceptable carriers or excipients.

Thus, the compound and optionally another therapeutic or prophylacticagent and their physiologically acceptable salts and solvates can beformulated into pharmaceutical compositions for administration byinhalation or insufflation (either through the mouth or the nose) ororal, parenteral or mucosol (such as buccal, vaginal, rectal,sublingual) administration. In some embodiments, the administration isoptical (e.g. eyes drops applied directly to the eye). In oneembodiment, local or systemic parenteral administration is used.

For oral administration, the compositions can take the form of, forexample, tablets or capsules prepared by conventional means withpharmaceutically acceptable excipients such as binding agents (e.g.,pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talcor silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulfate). The tabletscan be coated by methods well known in the art. Liquid preparations fororal administration can take the form of, for example, solutions, syrupsor suspensions, or they can be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations can be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetableoils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates orsorbic acid). The preparations can also contain buffer salts, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration can be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions can take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compositions for use according tothe present invention are conveniently delivered in the form of anaerosol spray presentation from pressurized packs or a nebulizer, withthe use of a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitcan be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g., gelatin for use in an inhaler orinsufflator can be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compositions can be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection can be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The pharmaceuticalcompositions can take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles, and can contain formulatory agents such assuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient can be in powder form for constitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

In addition to the formulations described previously, the compositionscan also be formulated as a depot preparation. Such long actingformulations can be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the pharmaceutical compositions can be formulated withsuitable polymeric or hydrophobic materials (for example as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

The compositions can, if desired, be presented in a pack or dispenserdevice that can contain one or more unit dosage forms containing theactive ingredient. The pack can for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device can beaccompanied by instructions for administration.

In certain preferred embodiments, the pack or dispenser contains one ormore unit dosage forms containing no more than the recommended dosageformulation as determined in the Physician's Desk Reference (62^(nd) ed.2008, herein incorporated by reference in its entirety).

Methods of administering the active compound and optionally anothertherapeutic or prophylactic agent include, but are not limited to,parenteral administration (e.g., intradermal, intramuscular,intraperitoneal, intravenous and subcutaneous), epidural, and mucosal(e.g., intranasal, rectal, vaginal, sublingual, buccal or oral routes).In a specific embodiment, the active compound and optionally anotherprophylactic or therapeutic agents are administered intramuscularly,intravenously, or subcutaneously. The active compound and optionallyanother prophylactic or therapeutic agent can also be administered byinfusion or bolus injection and can be administered together with otherbiologically active agents. Administration can be local or systemic. Theactive compound and optionally the prophylactic or therapeutic agent andtheir physiologically acceptable salts and solvates can also beadministered by inhalation or insufflation (either through the mouth orthe nose). In a preferred embodiment, local or systemic parenteraladministration is used.

In specific embodiments, it can be desirable to administer the activecompound locally to the area in need of treatment. This can be achieved,for example, and not by way of limitation, by local infusion duringsurgery or topical application, e.g., in conjunction with a wounddressing after surgery, by injection, by means of a catheter, by meansof a suppository, or by means of an implant, said implant being in oneembodiment of a porous, non-porous, or gelatinous material, includingmembranes, such as silastic membranes, or fibers.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the active compound can be formulated as asuppository, with traditional binders and vehicles such astriglycerides.

Selection of a particular effective dose can be determined (e.g., viaclinical trials) by a skilled artisan based upon the consideration ofseveral factors, which will be known to one skilled in the art. Suchfactors include the disease to be treated or prevented, the symptomsinvolved, the subject's body mass, the subject's immune status and otherfactors known by the skilled artisan.

The dose of the active compound to be administered to a subject, such asa human, is rather widely variable and can be subject to independentjudgment. It is often practical to administer the daily dose of theactive compound at various hours of the day. However, in any given case,the amount of the active compound administered will depend on suchfactors as the solubility of the active component, the formulation used,subject condition (such as weight), and/or the route of administration.

EXAMPLES

The following examples are provided in order to demonstrate and furtherillustrate certain preferred embodiments and aspects of the presentinvention and are not to be construed as limiting the scope thereof.

In the experimental disclosure which follows, the followingabbreviations apply: N (normal); M (molar); mM (millimolar); μM(micromolar); mol (moles); mmol (millimoles); μmol (micromoles); nmol(nanomoles); pmol (picomoles); g (grams); mg (milligrams); μg(micrograms); ng (nanograms); 1 or L (liters); μl (milliliters);(microliters); cm (centimeters); mm (millimeters); μm (micrometers); nm(nanometers); C (degrees Centigrade); TLC (thin layer chromatography).

Example I

As shown in FIG. 3B (the specific route from 8 to 14), commerciallyavailable 8 was coupled to the boronic acid tris anhydride 9 usingSuzuki reaction conditions to give 10 in 96% yield. Treatment of 10 withethylvinyl ether/Br2/diisopropylamine/CH₂Cl₂ at 0° C. resulted in theether 12 in 99% yield. 12 was then combined with CsF (3.22 eq) indimethylformamide under reflux conditions (130° C.) to give 14 in 90%yield. The structure of 14 was determined via X-ray analysis. Theoverall yield from 8 to 14 via 10 and 12 is 85.5% for the three steps.In an alternative embodiment, the same sequence of reactions may beperformed with the SiMe₂But (tert-butyldimethylsilyl) protected phenolderivative 9a, which provides the cross-conjugated 2,5-cyclohexadienone14 in three steps from 8 via 11 and 13 in an overall yield of 94.1%.

As shown in FIG. 4B (the specific route from 14 to 19), Treatment of 14with nitromethane under Henry aldol reaction conditions results in 15 atan unoptimized yield of 97% as a mixture (1:1) of epimers at the C₁₆site. These epimers were characterized by X-ray crystallography. It isnoteworthy that only the correct cis-stereochemical relationship betweenthe newly formed B-ring and the C-ring, i.e. at the C₁₃ and C₁₄positions, is observed in 15.

The stereogenic center at C₁₆ in 15, 16 and 17 is eventually removed bythe conversion of 17 into 18, as shown in FIG. 4B. Treatment of 15 withsodium cyanoborohydride gave 16 in 90% yield, which on further reductionwith lithium aluminum hydride gave 17 (72% yield). The intramolecularreductive amination of 17 gave 18. The yields in these conversions arenot optimized, but are clean reactions with no discernible by-products.The compound 18 was characterized as the known carbamate derivative 19from the Taber synthesis of morphine.

The third and final phase involves the conversion of 19 into codeine 4.The prior literature dealing with this topic involves proceeding viacodeinone 3 followed by reduction to 4. While not limiting the presentinvention to any particular theory, it is believed that the epoxidationof the 6,7-double bond proceeds from the least hindered face to give theR-epoxide, which eventually requires stereochemical inversion at C₆. Asshow in FIG. 5B, treatment of 19 with 3,3-dimethyl-1,5-dibromohydantoingave 20 (97% yield). Exposure to KOH and PhH under reflux conditionsresulted in the β-epoxide 21 (93% yield) with concomitant bromination atthe C₂ position. Treatment of 21 with PhSNa/EtOH gave 22 (99% yield),and the derived sulfoxide thermally eliminated to give 23 (93% yield).Reduction of 23 with LiAlH₄/THF at 25° C. converted 23 into codeine 4(87% yield).

Example II

In the following example, melting points were taken on a Thomas-Hoovercapillary tube apparatus, and are uncorrected. Infrared spectra wererecorded on a Thermo-Nicolet Avatar 360 FT-IR spectrophotometer, withthe sample neat on KBr plates, unless otherwise indicated. ¹H and ¹³CNMR spectra were recorded on a General Electric QE-300 spectrometer at300 MHz, in the indicated solvent, and are reported in ppm relative totetramethylsilane, or referenced internally to the residually protonatedsolvent. Mass spectra were obtained on a VG ZAB2E, or a Finnigan TSQ70mass spectrometer.

Routine monitoring of reactions was performed using Merck 60 F₂₅₄glass-backed silica gel TLC plates. Flash column chromatography wasperformed using EMD silica gel (particle size 0.040-0.063 μm). Solventsand commercial reagents were purified as disclosed in Perrin et al.Purification of Laboratory Chemicals; 3^(rd) edition; Permagon Press:New York, 1993, or used without further purification. All reactions wereconducted under an argon atmosphere, and solvents were degassed onlywhen specified.

(4-Bromo-Phenoxy)-Triisopropylsilane

To a stirred solution of 4-bromophenol (25.1 g, 146 mmol), and imidazole(19.9 g, 292 mmol) in 1,2-dichloroethane (150 mL) at 23° C. was addedtriisopropylsilylchloride (34.4 mL, 161 mmol). The mixture was stirredfor 12 h and poured onto saturated aqueous NH₄Cl (400 mL), followed byextraction with CH₂Cl₂ (3×200 mL). The combined extracts were washedwith brine (300 mL), dried (Na₂SO₄), and concentrated in vacuo to give apale yellow oil which was crude oil was purified via short-pathdistillation (0.5 mmHg, 130° C.) to yield(4-Bromo-phenoxy)-triisopropylsilane as a colorless oil (53.0 g, 99%yield). R_(f) 0.81 (3:1 hexanes/EtOAc) IR (thin film) 2945, 2892, 2867cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 7.30 (2H, d, J=9 Hz), 6.75 (2H, d, J=9Hz), 1.29-1.18 (3H, m), 1.08 (18H, d, J=7 Hz). ¹³C NMR (75 MHz, CDCl₃) δ155.0, 132.0, 121.5, 112.9, 17.6, 12.4. HRMS calcd. for C₁₅H₂₆OSiBr(MH⁺) 329.0936, found 329.0937.

2-Bromo-3-Hydroxy-4-Methoxy-Benzaldehyde (8)

To a stirred suspension of isovanillin (10 g, 66 mmol), powderedanhydrous sodium acetate (10.82 g, 0.132 mol) and iron powder (0.3 g,5.4 mmol) in glacial acetic acid (60 mL) under argon, was addeddrop-wise over 15 min a solution of Br₂ (3.7 mL, 0.0726 mol) in aceticacid (12.5 mL). The reaction temperature rose during the course ofaddition, and the mixture became viscous. After all the startingmaterial was consumed, as determined by TLC, the mixture was poured ontoice cold water, and the resulting precipitate filtered under vacuum. Theprecipitate was washed several times with cold water and air-dried.Crystallization from boiling ethanol gave 8 (11.93 g, 79% yield) as agray powder. R_(f)=0.10 (1:5 EtOAc/hexanes). M.p. 196-200° C. IR (thinfilm) 3215, 1662, 1588, 1561, 1491, 1273 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ10.27 (1H, s), 7.59 (1H, d, J=9 Hz), 6.96 (1H, d, J=9 Hz), 6.02 (1H,bs), 4.00 (3H, s). ¹³C NMR (75 MHz, CDCl₃) δ 56.58, 109.24, 112.84,113.84, 122.74, 143.25, 151.65, 190.87. HRMS calcd. for C₈H₈O₃Br (MH⁺)230.9657. Found 230.9652.

2,4,6-Tris-(4-Triisopropylsilanyloxy-Phenyl)-Cyclotriboroxane (9)

To a solution of (4-bromo-phenoxy)-triisopropylsilane (18.6 g, 56.7mmol) in dry THF (500 mL) at −78° C. was added drop-wise a solution ofn-BuLi (45 mL, 79.4 mmol, 2.5 M in THF). The resulting yellow solutionwas stirred 70 min at −78° C. before drop-wise addition of freshlydistilled B(OPr^(i))₃ (36 mL, 160 mmol). The mixture was stirred 12 h at23° C. until all the starting material was consumed, as determined bythin layer chromatography (TLC). The mixture was combined with 10%aqueous KHSO₄ (300 mL), and extracted with EtOAc (3×200 mL). Thecombined extracts were washed with brine (200 mL), dried (Na₂SO₄) andconcentrated in vacuo to yield an off-white solid. The crude solid waspurified by flash column chromatography (SiO₂, 20% EtOAc/hexanes) togive a waxy white solid, which on azeotroping in toluene gave 9 (12.68g, 76% yield) as a chalky white solid. M.p. 220° C. (hexanes). R_(f)0.51 (1:1 hexanes/EtOAc). IR (thin film) 3035, 2944, 2892, 2867 cm⁻¹. ¹HNMR (300 MHz, CDCl₃) δ 8.11 (6H, d, J=8 Hz), 7.00 (6H, d, J=8 Hz),1.35-1.28 (9H, m), 1.14 (54H, d, J=8 Hz). ¹³C NMR (75 MHz, CDCl₃) δ159.9, 137.2, 122.6, 119.4, 17.7, 12.5. HRMS calcd. for C₄₅H₇₆B₃O₆Si₃(MH⁺) 829.5229. Found 829.5227.

6-Hydroxy-5-Methoxy-4′-(Triisopropylsilanyloxy)-Biphenyl-2-Carbaldehyde(R=TIPS) (10)

To a degassed (30 min) mixture of 1,4-dioxane (9 mL) and water (4 mL)was added powdered K₂CO₃ (1.13 g, 8.16 mmol), 8 (0.687 g, 2.99 mmol), 9(0.750 g, 2.72 mmol), 2,6-di-tent-butyl-4 methylphenol (BHT) (0.300 g,1.36 mmol), and tricyclohexylphoshine (61 mg, 0.218 mmol). The mixturestirred for 15 min at 23° C. and [Pd₂(dba)₃] (0.100 g, 0.109 mmol) wasadded, and then heated at reflux for 1 h until all starting material wasconsumed, as determined by thin layer chromatography (TLC). Theresulting dark colored mixture was poured onto saturated aqueous NH₄Cl(20 mL) and extracted with EtOAc (5×25 mL). The combined extracts werewashed with brine (20 mL), dried (Na₂SO₄) and concentrated in vacuo toyield an orange oil. The crude oil was purified via flash columnchromatography (SiO₂, 20% EtOAc/hexanes) to give 10 (1.05 g, 96% yield)as a thick yellow-orange oil. R_(f) 0.61 (CH₂Cl₂). IR (thin film) 3538,2945, 2892, 2867, 1683 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 9.68 (1H, s),7.64 (1H, d, J=9 Hz), 7.26-7.22 (2H, m), 7.01-6.96 (3H, m), 5.68 (1H,s), 4.01 (3H, s), 1.33-1.26 (3H, m), 1.13 (18H, d, J=7 Hz). ¹³C NMR (75MHz, CDCl₃) δ 191.4, 155.8, 150.8, 142.3, 131.7, 129.1, 128.2, 124.5,120.6, 119.5, 109.2, 56.0, 17.7, 12.5. HRMS calcd. for C₂₃H₃₃O₄Si (MH⁺)401.2148. Found 401.2148.

6-(2-Bromo-1-Ethoxy-Ethoxy)-5-Methoxy-4′-Triisopropylsilanyloxy-Biphenyl-2-Carbaldehyde(R=TIPS) (12)

To a solution of bromine (0.91 mL, 17.8 mmol) in CH₂Cl₂ (50 mL) at 0° C.was added drop-wise ethyl vinyl ether (2.13 mL, 22.2 mmol). Theresulting colorless solution was stirred for 20 min at 0° C. andN,N-diisopropylamine (DIEA) (6.23 mL, 35.6 mmol) added drop-wise,followed by a CH₂Cl₂ (20 mL) solution of 10 (3.55 g, 8.9 mmol). Theresulting solution was stirred for 16 h at 23° C., until all startingmaterial was consumed, as determined by TLC. The mixture was poured ontosaturated aqueous NaHCO₃ (100 mL), and extracted with CH₂Cl₂ (3×70 mL).The combined extracts were washed with brine (80 mL), dried (Na₂SO₄),and concentrated in vacuo to yield orange oil. The crude oil waspurified via flash column chromatography (SiO₂, 10% EtOAc/hexanes) togive 12 (4.84 g, 99% yield) as a thick orange oil. R_(f) 0.52 (3:1hexanes/EtOAc). IR (thin film) 2966, 2944, 2892, 2867, 1684 cm⁻¹. ¹H NMR(300 MHz, CDCl₃) δ 9.64 (1H, s), 7.85 (1H, d, J=8 Hz), 7.25-7.18 (2H,m), 7.03 (1H, d, J=8 Hz), 6.96 (2H, d, J=8 Hz), 5.06-5.02 (1H, m), 3.98(3H, s), 3.65-3.55 (1H, m), 3.42-3.34 (1H, m), 3.12-3.01 (2H, m),1.35-1.20 (3H, m), 1.13 (18H, d, J=7 Hz), 1.05 (3H, t, J=7 Hz). ¹³C NMR(75 MHz, CDCl₃) δ 191.1, 156.9, 156.1, 141.5, 140.5, 132.4, 128.4,125.1, 119.4, 113.6, 111.0, 103.5, 64.5, 55.9, 31.7, 17.8, 14.9, 12.5.HRMS calcd. for C₂₇H₄₀O₅SiBr (MH⁺) 551.1828. Found 551.1821.

Cross-Conjugated Cyclohexadienone (14)

A suspension of dry CsF (0.490 g, 3.22 mmol) and 12 (0.590 g, 1.07 mmol)in DMF (11 mL, stored over activated 4 Å molecular sieves) were heatedat reflux for 2 h. After all starting material was consumed, asdetermined by TLC, the mixture was poured onto saturated aqueous NaHCO₃(100 mL) and extracted with EtOAc (3×70 mL). The combined extracts werewashed with brine (80 mL), dried (Na₂SO₄), and concentrated in vacuo toyield orange oil which was purified via flash column chromatography(SiO₂, 25% EtOAc/hexanes) to give 14 (0.302 g, 90% yield) as thickorange oil which solidified upon standing to a orange solid. M.p. 74-80°C. R_(f)=0.23 (1:1 EtOAc/hexanes). IR (thin film) 2983, 2932, 2889,1684, 1663, 1586 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 9.95 (s, 1H), 7.75 (1H,dd, J's=10, 3 Hz), 7.64 (1H, d, J=9 Hz), 7.04 (1H, J's=10, 3 Hz), 6.98(1H, d, J=9 Hz), 6.38 (1H, dd, J's=8, 2 Hz), 6.36 (1H, dd, J's=8, 2 Hz),5.15 (1H, t, J=2 Hz), 4.00 (s, 3H), 3.96 (1H, m), 3.70 (1H, m), 2.40(1H, dd, J's=14, 2 Hz), 2.01 (1H, dd, J's=14, 2 Hz), 1.22 (3H, t, J=7Hz). ¹³C NMR (75 MHz, CDCl₃) δ 189.6, 184.4, 155.8, 155.5, 154.5, 140.1,128.7, 126.0, 123.3, 122.8, 110.7, 94.8, 64.7, 56.2, 40.2, 39.8, 15.0.HRMS calcd. for C₁₈H₁₉O₅ (MH⁺) 315.1232. Found 315.1231.

(4-Bromo-Phenoxy)-Tert-Butyl-Dimethylsilane

To a stirred solution of p-bromophenol (30 g, 0.1734 mol) in1,2-dichloroethane (300 mL) at 23° C. was added imidazole (29.45 g,0.433 mol). After 15 min, tert-butyldimethylsilylchloride (28.75 g,0.190 mol) was added, and the resulting solution heated at reflux for 3h. The mixture was cooled to room temperature and poured onto saturatedaqueous NH₄Cl and extracted with CH₂Cl₂ (3×200 mL). The combinedextracts were washed with brine (200 mL), dried (NaSO₄), filtered andevaporated in vacuo. The crude product was distilled via short-pathdistillation (0.5 mm Hg, 130° C.) to give(4-bromo-phenoxy)-tert-butyl-dimethylsilane (49.6 g, 99.5% yield) as acolorless oil. R_(f)=0.80 (1:3 EtOAc/hexanes). IR (thin film) 3390,2951, 2928, 1584, 1479, 1250 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 7.34 (1H,d, J=9 Hz), 6.74 (1H, d, J=9 Hz), 1.00 (12H, s), 0.21 (6H, s). ¹³C NMR(75 MHz, CDCl₃) δ 154.76, 132.22, 121.83, 113.55, 25.58, 18.12, −4.54.HRMS calcd. for C₁₂H₂₀BrOSi (MH⁺) 287.0461. Found 287.0463.

2,4,6-Tris-[4-(Tert-Butyl-Dimethyl-Silanyloxy)-Phenyl]-Cyclotriboroxane(9a)

To a solution of (4-bromo-phenoxy)-tert-butyl-dimethylsilane (10 g, 35mmol) in THF (25 mL) at −78° C. was added drop-wise n-butyllithium (2.4M in hexanes, 17.5 mL, 42 mmol) resulting in a yellow colored solution.After stirring the mixture for 30 min, freshly distilledtriisopropoxyborate (24.2 mL, 105 mmol) was added drop-wise to the abovesolution, and the mixture was stirred overnight and allowed to warm toroom temperature. The mixture was poured onto 10% aqueous KHSO₄ (50 mL)and extracted with EtOAc (3×150 mL). The combined extracts were washedwith brine (200 mL), dried (Na₂SO₄), filtered and evaporated in vacuo.The crude white solid was dried by azeotroping in toluene (3×20 mL), andrecrystallized from hexanes/EtOAc to give needle shaped crystals of 9a(6.9 g, 84.5% yield). M.p. 118-120° C. R_(f)=0.12 (1:5 EtOAc/hexanes).IR (thin film) 2955, 2928, 2854, 1592 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ8.13 (2H, d, J=8 Hz), 6.97 (2H, d, J=8 Hz), 1.03 (9H, s), 0.27 (2H, s).¹³C NMR (75 MHz, CDCl₃) δ 159.7, 137.4, 119.8, 25.7, 18.3, −4.3. HRMScalcd. for C₃₆H₅₈B₃O₆Si₃ (MH⁺) 703.3820. Found 703.3826.

4′-(Tert-Butyl-Dimethyl-Silanyloxy)-6-Hydroxy-5-Methoxy-Biphenyl-2-Carbaldehyde(R=TBDMS) (11)

To a degassed (30 min) mixture of 1,4-dioxane (22.5 mL) and water (7.5mL) was added powdered K₂CO₃ (2.48 g, 18 mmol), 8 (1.53 g, 6.6 mmol), 9a(1.5 g, 6 mmol), 2,6-di-tert-butyl-4 methylphenol (BHT) (spatula), andtricyclohexylphoshine (67 mg, 0.24 mmol). The mixture stirred for 15 minat 23° C. and [Pd₂(dba)₃] (0.114 g, 0.12 mmol) was added, and thenheated at reflux for 1 h until all starting material was consumed, asdetermined by TLC. The resulting dark colored solution was poured ontosaturated aqueous NH₄Cl (200 mL) and extracted with EtOAc (3×150 mL).The combined extracts were washed with brine (200 mL), dried (Na₂SO₄)and concentrated in vacuo to yield a yellow solid. Purification by flashcolumn chromatography (SiO₂, 15% EtOAc/hexanes) gave 11 (2.1 g, 87.9%yield) as a pale yellow solid. M.p. 103-106° C. R_(f)=0.20 (1:5EtOAc/hexanes). IR (thin film) 3401, 2930, 2857, 1684 cm⁻¹. ¹H NMR (300MHz, CDCl₃) δ 9.69 (1H, s), 7.65 (1H, d, J=9 Hz), 7.24 (1H, d, J=9 Hz),6.98 (1H, d, J=9 Hz), 6.95 (1H, d, J=9 Hz), 5.67 (1H, bs), 4.02 (3H, s),1.02 (9H, s), 0.26 (6H, s). ¹³C NMR (75 MHz, CDCl₃) δ 191.6, 155.7,150.8, 142.7, 132.0, 131.5, 128.4, 120.5, 119.8, 109.6, 56.2, 25.6,18.2, −4.4. HRMS calcd. for C₂₀H₂₇O₄Si (MH⁺) 359.1679. Found 359.1675.

Conducting the above reaction on the following scale— K₂CO₃ (4.48 g,32.4 mmol), 8 (2.75 g, 11.88 mmol), 9a (2.54 g, 10.8 mmol),2,6-di-tert-butyl-4 methylphenol (BHT) (1.19 g, 5.4 mmol),tricyclohexylphoshine (0.24 g, 0.864 mmol), [Pd₂(dba)₃] (0.40 g, 0.432mmol) in dioxane (36 mL) and water (15.5 mL) gave 11 (3.836 g, 99%yield).

6-(2-Bromo-1-Ethoxy-Ethoxy)-4′-(Tert-Butyl-Dimethyl-Silanyloxy)-5-Methoxy-Biphenyl-2-Carbaldehyde(R=TBDMS) (13)

To a solution of Br₂ (0.397 mL, 7.74 mmol) in CH₂Cl₂ (30 mL) at 0° C.was added drop-wise ethyl vinyl ether (0.92 mL, 9.68 mmol) until thesolution turned colorless. The mixture was stirred for 15 min anddiisopropylethyamine (2.71 mL, 15.48 mmol) was added followed by adrop-wise addition of a solution of 11 (1.5 g, 3.87 mmol) in CH₂Cl₂ (15mL) The mixture was stirred for 12 h under an argon atmosphere to givean orange-red solution. After complete consumption of staring material,as determined by TLC. the mixture was poured onto saturated aqueousNaHCO₃ and extracted with CH₂Cl₂ (3×50 mL). The combined extracts werewashed with brine (100 mL), dried (Na₂SO₄), filtered and evaporated invacuo to give an orange-red oil. Purification by flash columnchromatography (SiO₂, 10% EtOAc/Hexanes) gave 13 (1.92 g, 92% yield) asa colorless syrupy liquid. (1.92 g, 92% yield). R_(f)=0.42 (1:5EtOAc/hexanes). IR (thin film) 2956, 2930, 2857, 1684 cm⁻¹. ¹H NMR (300MHz, CDCl₃) δ 9.64 (1H, s), 7.85 (1H, d, J=9 Hz), 7.25-7.18 (2H, m),7.03 (1H, d, J=9 Hz), 6.93 (2H, d, J=9 Hz), 5.01 (1H, dd, J's=7, 4 Hz),3.98 (3H, s), 3.56 (1H, m), 3.31 (1H, m), 3.09 (2H, m), 1.05 (2H, t, 7Hz), 1.01 (9H, s), 0.24 (6H, s). ¹³C NMR (75 MHz, CDCl₃) δ 191.5,157.02, 155.8, 141.7, 140.6, 132.5, 128.5, 125.2, 119.7, 111.0, 103.7,64.5, 55.9, 31.8, 25.6, 18.2, 14.9, −4.4. HRMS calcd. for C₂₄H₃₄O₅SiBr(MH⁺) 509.1359. Found 509.1356.

Conducting the above reaction on the following scale— Br₂ (1.64 mL, 32mmol) in CH₂Cl₂ (126 mL), ethyl vinyl ether (3.8 mL, 40 mmol),diisopropylethyamine (11.2 mL, 64 mmol) 11 (5.73 g, 16 mmol) gave 13(8.10 g, 99% yield).

Cross-Conjugated Cyclohexadienone (14)

A flame-dried mixture of CsF (0.22 g, 1.44 mol) and Na₂SO₄ (0.68 g, 4.8mmol) was added to a solution of 13 (0.26 g, 0.48 mmol) in DMF (3.7 mL,stored over 4 Å molecular sieves) and the reaction mixture was heated at130° C. for 1.5 h. After completion of the reaction, as determined byTLC, the reaction mixture was poured into saturated aqueous NaHCO₃ (25mL) and extracted with EtOAc (4×20 mL). The combined extracts weresuccessively washed with water (3×25 mL), brine (50 mL), dried (Na₂SO₄),filtered and concentrated in vacuo to give a brown syrup. Purificationby flash chromatography (SiO₂, 30% EtOAc/hexanes) gave compound 14(0.137 g, 95.5% yield).

Conducting the above reaction on the following scale: 13 (7.0 g, 13.8mmol), CsF (6.5 g, 41.3 mmol) in DMF (138 mL) gave 14 (4.24 g, 94%).

6-Ethoxy-8-Methoxy-12-Nitro-1,5,6,12a-Tetrahydro-Naphtho[8a,1,2-de]Chromen-2-One(15)

A mixture of the dienone 14 (1.0 g, 3.18 mmol), NH₄OAc (0.98 g, 12.7mmol), and nitromethane (1.01 mL, 19.08 mmol) in acetic acid (15 mL) washeated at reflux for 2 h. After completion of the reaction, asdetermined by TLC, the solvent was evaporated in vacuo and the residuewas washed with water (40 mL) and extracted with diethylether (3×50 mL).The combined extracts were washed with brine (50 mL), dried (Na₂SO₄),filtered and concentrated in vacuo to give a brown solid. Purificationby flash chromatography (SiO₂, 20% EtOAc/hexanes) gave bright yellowcrystals of the two diastereomers 15 and 15a (0.72 g, 63% yield) inapproximately 1:1 ratio. Data for 15. R_(f)=0.47 (1:1 EtOAc/hexanes).M.p. 165-170° C. IR (thin film) 2920, 2842, 1685, 1565 cm⁻¹. ¹H NMR (300MHz, CDCl₃) δ 7.56 (1H, d, J=2 Hz), 6.96 (1H, d, J=8 Hz), 6.86 (1H, d,J=8 Hz), 6.48 (1H, dd, J's=10, 2 Hz), 5.98 (1H, d, J=10 Hz), 5.38 (1H,dd, J's=9, 3 Hz), 4.16 (1H, m), 3.92 (3H, s), 3.74 (1H, m), 3.50 (1H,m), 3.28 (1H, dd, J's=6, 2 Hz), 2.89 (1H, dd, J's=18, 5 Hz), 2.66 (1H,dd, J's=13, 3 Hz), 2.27 (1H, dd, J's=13, 9 Hz), 1.29 (3H, t, J=7 Hz).¹³C NMR (75 MHz, CDCl₃) δ 194.6, 150.0, 146.9, 141.4, 132.2, 128.7,123.9, 121.3, 111.3, 97.7, 65.3, 56.1, 42.1, 39.1, 38.8, 34.2, 15.1.HRMS calcd. for C₁₉H₂₀NO₆ (MH⁺) 358.1291. Found 358.1290.

Data for 15a. R_(f)=0.47 (1:1 EtOAc/Hexanes). M.p. 161-164° C. 1R (thinfilm) 2974, 2926, 2853, 1684, 1570 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 7.58(1H, d, J=2 Hz), 7.00 (1H, d, J=9 Hz), 6.90 (1H, d, J=9 Hz), 6.75 (1H,dd, J's=10, 1.5 Hz), 5.92 (1H, d, J=10 Hz), 5.59 (1H, d, J=3 Hz), 3.95(1H, m), 3.96 (3H, s), 3.70 (1H, m), 3.45 (1H, dd, J's=4, 2 Hz), 3.27(1H, dd, J=9, 1.5 Hz), 2.88 (1H, dd, J=18, 5 Hz), 2.70 (1H, dd, J's=13,1.5 Hz), 2.33 (1H, dd, J's=13, 3 Hz), 1.20 (3H, t, J=7 Hz). ¹³C NMR (75MHz, CDCl₃) δ 194.9, 152.3, 147.4, 140.4, 132.2, 126.9, 123.9, 121.3,110.9, 96.2, 68.1, 64.6, 56.1, 43.1, 37.2, 36.2, 34.4, 29.64, 15.1.

Example III

To the dienone 14 (5.0 g, 15.93 mM) in nitromethane (50 mL), was addedNH₄OAc (0.5 g) and acetic acid (5 mL) and the solution was heated atreflux for 2.5 h. When 14 had been consumed (TLC), the mixture waspoured into brine (50 mL) and the layers separated. The aqueous layerwas successively washed with ether (2×40 mL). The combined organics weredried (Na₂SO₄) and concentrated in vacuo to give (5.5 g, 97% yield) of15/15a as a racemic mixture of two diastereomers in a 1:1 ratio. NMRanalysis indicated that the crude mixture was pure enough to be carriedforward without purification.

6-Ethoxy-8-Methoxy-12-Nitro-1,5,6,11,12,12a-Hexahydro-Naphtho[8a,1,2-de]Chromen-2-One(16)

To a solution of the nitroalkenes 15/15a (127 mg, 0.36 mmol) in THF (3.5mL) and phosphate buffer (pH 4.5, 1.5 mL) at 0° C. was added NaBH₃CN(23.5 mg, 0.37 mmol) in small portions, and the resulting solution wasstirred for 1 h until all the starting material was consumed asdetermined by TLC. The mixture was combined with aqueous NH₄Cl (5 ml)and extracted with EtOAc (3×5 mL). The combined organic extracts werewashed with brine (15 mL), dried (Na₂SO₄), filtered and concentrated invacuo to give a pale yellow solid. Purification by flash columnchromatography (SiO₂, 30% EtOAc/hexanes) gave 16 and 16a as white solids(112 mg, 88% yield). R_(f)=0.55 (1:1 EtOAc/Hexanes). Data for 16. M.p.168° C. IR (thin film) 2975, 2932, 1684, 1551 cm⁻¹. ¹H NMR (300 MHz,CDCl₃) δ 6.84 (1H, d, J=9 Hz), 6.82 (1H, dd, J's=10, 4 Hz), 6.73 (1H, d,J=9 Hz), 6.06 (1H, d, J=10 Hz), 5.50 (1H, dd, J's=8, 6 Hz), 4.92 (1H,m), 4.10 (1H, m), 3.88 (3H, s), 3.67 (1H, m), 3.33 (2H, m), 2.86 (3H,m), 2.46 (1H, d, J=18 Hz), 2.00 (1H, dd, J's=13, 8 Hz), 0.26 (3H, t, J=7Hz). ¹³C NMR (75 MHz, CDCl₃) δ 194.0, 152.0, 148.6, 141.0, 128.5, 125.2,122.2, 121.5, 112.5, 98.2, 83.8, 64.4, 56.2, 43.6, 42.4, 38.1, 35.9,33.2, 14.9. HRMS calcd. for C₁₉H₂₂NO₆ (MH⁺) 360.1447. Found 360.1443.

Data for 16a. R_(f)=0.55 (1:1 EtOAc/Hexanes). M.p. 201° C. IR (thinfilm) 2975, 2932, 1685, 1551 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 6.87 (2H,m), 6.06 (1H, d, J=10 Hz), 5.50 (1H, dd, J's=8, 6 Hz), 4.92 (1H, m),4.10 (1H, m), 3.88 (3H, s), 3.67 (1H, m), 3.33 (2H, m), 2.86 (3H, m),2.46 (1H, d, J=18 Hz), 2.00 (1H, dd, J's=13, 8 Hz), 0.26 (3H, t, J=7Hz). ¹³C NMR (75 MHz, CDCl₃) δ 194.0, 152.0, 148.6, 141.0, 128.5, 125.2,122.2, 121.5, 112.5, 98.2, 83.8, 64.4, 56.2, 43.6, 42.4, 38.1, 35.9,33.2, 29.6, 14.9; HRMS calcd. for C₁₉H₂₂NO₆ (MH⁺) 360.1447. Found360.1443.

12-Amino-6-Ethoxy-8-Methoxy-1,5,6,11,12,12a-Hexahydro-2H-Naphtho[8a,1,2-de]Chromen-2-Ol(17/17a)

To a solution of the nitroalkanes 16/16a (468 mg, 1.3 mmol) in THF (15ml) cooled to −78° C. under argon, was added LiAlH₄ (2M in THF, 3.9 mL)drop-wise over a 20 minute interval. The resulting solution was stirredat −78° C. for 1 h and allowed to warm to room temperature (RT) over 8h. The reaction was checked for completion by TLC, and then added tosaturated aqueous Na₂SO₄ (5 ml) at 0° C. The salts were filtered througha Buchner funnel and washed with (100 ml) of ether. The organic layerwas washed with brine (15 ml), dried (Na₂SO₄), and concentrated in vacuoto yield a pale yellow foamy solid. The crude product can be purified bycolumn chromatography (SiO₂, 1% NEt₃, 10% MeOH, 89% CH₂Cl₂) to yield awhite foamy solid (312 mg, 72%). R_(f)=0.26 (15% MeOH/CH₂Cl₂). Data for17. IR (thin film) 3352, 3287, 2924, 1497, 1439 cm⁻¹. ¹H NMR (300 MHz,CDCl₃) δ 6.84 (1H, d, J=8 Hz), 6.71 (1H, d, J=9 Hz), 6.00 (1H, d, J=10Hz), 5.90 (1H, dd, J's=10, 3 Hz), 5.50 (1H, dd, J's=8, 6.6 Hz),4.42-4.17 (1H, m), 4.11-4.05 (1H, m), 3.86 (3H, s), 3.83-3.61 (1H, m),3.42-3.90 (1H, m), 3.05 (1H, dd, J's=16, 3 Hz), 2.76 (1H, dd, J's=16, 3Hz), 2.60 (1H, dd, J's=12.5, 6 Hz), 2.50 (1H, m), 2.02 (2H, m), 2.02(1H, bd, 15 Hz), 1.57 (1H, dd, J's=12.5, 8 Hz), 1.21 (3H, t, J=7 Hz).¹³C NMR (75 MHz, CDCl₃) δ 148.4, 141.6, 132.2, 131.0, 127.7, 123.3,122.4, 111.6, 99.2, 65.8, 64.2, 59.8, 56.2, 49.8, 44.8, 38.2, 34.6,31.1, 15.1. HRMS calcd. for C₁₉H₂₆NO₄ (MH⁺) 332.1859, found 332.1856.Data for 17a. R_(f)=0.21 (15% MeOH/CH₂Cl₂). IR (thin film) 3342, 3287,2924, 2856, 1493, 1441, 1375, 1260, 1210, 1123, 1035, 1009 cm⁻¹. ¹H NMR(300 MHz, CDCl₃) δ 6.77 (1H, d, J=8 Hz), 6.69 (1H, d, J=8 Hz), 5.89 (1H,d, J=10 Hz), 5.90 (1H, d, J=10 Hz), 5.50 (1H, d, J=2 Hz), 4.44-4.37 (1H,m), 4.05-3.90 (1H, m), 3.86 (3H, s), 3.85-3.62 (1H, m), 3.26 (1H, m),2.97 (2H, m), 2.67-2.34 (3H, m), 2.21 (2H, dd, J's=17, 7 Hz), 2.02-1.86(1H, m), 1.61 (1H, bs), 1.21 (311, t, J=7 Hz). ¹³C NMR (75 MHz, CDCl₃) δ147.4, 140.6, 135.9, 128.1, 127.0, 125.6, 120.8, 110.4, 97.7, 64.3,64.2, 56.2, 50.1, 45.8, 42.2, 38.1, 34.7, 33.1, 15.2.

Core Secondary Amine (18)

To a solution of the primary amines 17/17a (1.0 g, 3.02 mM) in dioxane(48 mL) was added 1N HCl (16 mL) and stirred for 10 mM NaCNBH₃ (569 mg,9.06 mM) was added in 3 portions after every 1 h. The mixture was takento reflux and heated at reflux for 5 h. The pH was maintained between2-3 by adding 1N HCl as required. The reaction was checked forcompletion by TLC, cooled to RT, and basified to pH 10 with 1M NaOH(aq.) and extracted with diethyl ether (5×25 mL). The combined organicswere washed with brine (30 mL), dried (Na₂SO₄) and conc. in vacuo toyield a brown syrup (730 mg).

The crude product can be purified by column chromatography (SiO₂, 1%NEt₃, 10% MeOH, 89% CH₂Cl₂) to yield pure 18 as a colorless syrup (540mg, 66% yield). R_(f)=0.12 (15% MeOH/CH₂Cl₂). IR (thin film) 3307, 3024,2920, 2847, 1634, 1504, 1439, 1278, 1256, 1194, 1159, 1127, 1063, 1037cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 6.71 (1H, d, J=8 Hz), 6.30 (1H, d, J=8Hz), 5.86 (1H, m), 5.71 (1H, m), 4.93 (1H, s), 3.86 (3H, s), 3.43 (1H,m), 3.00 (1H, dd, J's=12, 6 Hz), 2.84 (2H, m), 2.76 (1H, d, J=18 Hz),2.35 (1H, m), 1.96 (1H, t, J=6 Hz), 1.90 (1H, t, J=6 Hz), 1.80 (1H, m),1.45 (1H, m). ¹³C NMR (75 MHz, CDCl₃) δ 144.6, 143.1, 131.9, 129.5,127.1, 124.5, 118.4, 112.7, 87.7, 56.1, 51.9, 49.9, 41.5, 39.1, 38.8,30.7, 24.4. HRMS calcd. for C₁₇H₂₀NO₂ (MH⁺) 270.1494. Found 270.1498.

Ethyl Carbamate (19)

To a solution of the secondary amine 18 (0.70 g, 2.6 mmol) in CH₂Cl₂ (20ml) cooled to 0° C. was added triethylamine (1.81 mL, 13.0 mmol) andethyl chloroformate (0.62 mL, 6.5 mmol) dropwise over 2 min. Theresulting solution was stirred at 0° C. for 1 hour. After checking forcompletion by TLC, the reaction mixture was quenched with saturatedaqueous NH₄Cl (20 mL) and extracted with CH₂Cl₂ (3×20 mL). The combinedextracts were washed with brine (25 mL), dried (Na₂SO₄) and evaporatedin vacuo to give a pale yellow oil. The crude product can be purified bycolumn chromatography (SiO₂, 30% EtOAc/hexanes) to yield a colorlesssyrup (0.795 g, 89.6% yield). R_(f)=0.48 (30% EtOAc/hexanes). IR (thinfilm) 2978, 2931, 2838, 1695 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 6.73 (1H,d, J=8 Hz), 6.62 (1H, d, J=8 Hz), 5.85 (11 μm), 5.71 (1H, d, J=10 Hz)),4.95 (1H, s), 4.71 (major amide rotamer 0.60H, bs), 4.56 (minor amiderotamer 0.4 H, bs), 4.15 (2H, q, J=7.2 Hz), 4.1-3.93 (1H, m), 3.85 (3H,s), 3.06-2.86 (2H, m), 2.68 (1H, d, J=18 Hz), 2.30-2.25 (1H, m), 2.00(1H, dt, J's=18, 6 Hz), 1.90-1.70 (2H, m), 1.53-1.40 (1H, m), 1.27 (3H,t, J=7.2 Hz). ¹³C NMR (75 MHz, CDCl₃) Major rotamer: δ155.4, 144.9,143.4, 131.9, 128.5, 125.8, 124.4, 118.9, 113.3, 87.4, 61.4, 56.2, 50.1,41.1, 37.7, 35.0, 28.8, 24.0, 14.7. Minor rotamer: δ 155.0, 144.8,143.4, 131.6, 128.5, 125.6, 124.6, 118.9, 113.3, 87.4, 61.4, 56.2, 50.5,41.1, 37.7, 34.8, 29.0, 24.1, 14.6. HRMS calcd. for C₂₀H₂₄NO₄ (MH⁺)342.1705. Found 360.1699.

Bromohydrin (20)

To a solution of 19 (250 mg, 0.73 mmol) in acetone/H₂O (10:1, 11 mL) wasadded recrystallized 2,2 bromo-3,5 dimethylhydantoin (520 mg, 1.83 mmol)in small portions over 5 min. The entire set-up was covered withaluminum foil, placed in the dark and stirred for 12 h until all thestarting material was consumed as determined by TLC. The reactionmixture was quenched with saturated NH₄Cl (10 ml), diluted with water(10 ml) and extracted with ethyl acetate (3×15 ml). The combinedextracts were washed with brine (20 mL), dried (Na₂SO₄) and evaporatedin vacuo to give a yellow oil. The crude product can be purified bycolumn chromatography (SiO₂, 50% EtOAc/hexanes) to yield a colorlesssyrup (365 mg, 97%) or can be carried forward onto the next step withoutpurification. R_(f)=0.26 (1:1 EtOAc/hexanes). IR (thin film) 3420, 2978,2937, 2889, 1684 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 6.98 (1H, s), 4.83 (1H,d, J=7 Hz), 4.78 (Major rotamer 0.60H, bs), 4.63 (Minor rotamer 0.4H,bs), 4.11 (2H, q, J=7.2 Hz), 4.1-3.94 (1H, m), 3.89 (3H, s), 3.72-2.59(2H, m), 2.77-2.61 (1H, m), 2.52 (1H, bs), 2.00 (1H, dt, J's=17, 3.7Hz), 2.20 (1H, m), 1.75-1.70 (1H, m), 1.27 (3H, t, J=7.2 Hz); 1.07-0.95(1H, m). ¹³C NMR (75 MHz, CDCl₃) Major rotamer: δ 155.4, 145.1, 143.3,129.3, 125.2, 117.7, 113.5, 95.8, 70.5, 61.8, 60.4, 56.8, 50.2, 45.4,38.4, 37.8, 34.4, 31.9, 29.8, 14.6. Minor rotamer: δ 155.0, 145.1,143.3, 129.3, 125.2, 117.7, 113.5, 95.8, 70.2, 61.7, 60.4, 56.8, 50.6,45.4, 38.3, 38.2, 34.1, 31.9, 30.1, 14.7. HRMS calcd. for C₂₀H₂₄NO₄Br₂(MH⁺) 516.0021. Found 516.0018.

Epoxide (21)

To a solution of the bromohydrin 20 (365 mg, 0.71 mM) in toluene (15 mL)was added solid KOH (200 mg) and the mixture was heated at 80° C. for 3hours until all the starting material was consumed (TLC). The reactionmixture was cooled and diluted with water (15 ml) and extracted withethyl acetate (3×20 mL). The combined organics were washed with brine(10 mL), dried (Na₂SO₄) and conc. in vacuo to give a yellow oil. Thecrude product was purified by column chromatography (SiO₂, 40%EtOAc/hexanes) to yield 21 as a colorless syrup (295 mg, 95.6%).R_(f)=0.37 (1:1 EtOAc/hexanes). IR (thin film) 2963, 2926, 2850, 1695,1684 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 6.91 (1H, s), 4.87 (1H, d, J=3.7Hz), 4.70 (major amide rotamer 0.70H, bs), 4.56 (minor amide rotamer0.3H, bs), 4.13 (2H, q, J=7.3 Hz), 4.1-3.89 (1H, m), 3.86 (3H, s),3.30-2.23 (2H, m), 2.79-2.70 (2H, m), 2.53 (1H, d, J=18 Hz), 2.00 (2H,m), 1.79-1.68 (2H, m), 1.27 (3H, t, J=7.2 Hz); 1.15-1.06 (1H, m). ¹³CNMR (75 MHz, CDCl₃) Major rotamer: 8155.2, 146.1, 142.9, 129.2, 124.2,116.7, 112.0, 87.6, 61.4, 56.4, 53.5, 50.9, 49.8, 41.1, 37.3, 36.2,35.9, 29.9, 22.7, 14.5. Minor rotamer: δ 154.8, 146.1, 142.9, 129.2,124.0, 116.7, 112.0, 87.6, 61.5, 56.5, 53.5, 50.9, 50.2, 41.1, 37.2,36.3, 35.9, 30.2, 22.9, 14.6. HRMS calcd. for C₂₀H₂₃BrNO₅ (MH⁺)436.0760. Found 436.0758.

Alternatively, the epoxides 21 may be obtained by mixing a solution ofthe carbamate 19 (70 mg, 0.205 mM) in 1,4 dioxane (3 mL) and water (1mL) and further adding recrystallized 1,3 bromo-5,5 dimethyl hydantoin(60.0 mg, 0.21 mM) and stirring for 12 hours in the dark. After 19 wasconsumed (TLC), solid KOH (50 mg) was added and the solution was heatedat 80° C. for 2.5 h. After all the intermediate bromohydrin 20 wasconsumed (TLC), the solution was diluted with water (10 mL) andextracted with ethyl acetate (3×10 mL). The combined organics werewashed with brine (10 mL), dried (Na₂SO₄) and concentrated in vacuo togive a pale, yellow oil. The crude product was purified by columnchromatography (SiO₂, 40% EtOAc/hexanes) to yield 21 as a colorlesssyrup (81 mg, 91%).

Phenyl Sulfide (22)

To a solution of diphenyl disulfide (12 mg, 0.055 mmol) in EtOH (1.0 mL)was added NaBH₄ (4 mg, 0.11 mmol) portion-wise over 5 min. The resultingsolution was stirred for 15 min and then added drop-wise to a solutionof the epoxide 21 (16 mg, 0.037 mmol) in EtOH (1.0 mL). The resultingsolution was stirred at 25° C. for 2 h until all the substrate wasconsumed (TLC). The mixture was diluted with water (5 mL) and extractedwith CH₂Cl₂ (3×5 mL). The combined organics were washed with brine (5mL), dried (Na₂SO₄) and conc. in vacuo to give a pale yellow solid. Thecrude product was purified by column chromatography (SiO₂, 30%EtOAc/hexanes) to yield 22 as a white solid (20 mg, 99% yield).R_(f)=0.60 (40% EtOAc/hexanes). IR (thin film) 3446, 2936, 1684, 1487,1437, 1323, 1300, 1274, 1229, 1191, 1172, 1148, 1065, 1023 cm⁻¹. ¹H NMR(300 MHz, CDCl₃) δ 7.39 (2H, d, J=7.3 Hz), 7.30 (3H, m), 6.93 (1H, s),4.88 (1H, d, J=5 Hz), 4.69 (Major rotamer 0.60H, bs), 4.54 (Minorrotamer 0.4H, bs), 4.14 (2H, q, J=7.2 Hz), 4.07-3.91 (2H, m), 3.84 (3H,s), 3.36-3.28 (2H, m), 2.79-2.59 (2H, m), 2.39-2.34 (2H, m), 1.85-1.56(4H, m), 1.27 (3H, t, J=7.2 Hz); ¹³C NMR (75 MHz, CDCl₃) Major rotamer:8155.3, 145.8, 142.8, 132.3, 129.2, 127.7, 125.1, 116.6, 112.8, 89.0,68.4, 61.5, 60.3, 56.4, 50.5, 46.5, 42.5, 37.6, 36.2, 36.0, 29.9, 24.4,21.0, 14.6; Minor rotamer: δ 155.0, 145.8, 142.8, 133.2, 132.0, 130.7,129.2, 127.7, 124.8, 116.6, 112.8, 89.0, 68.4, 61.6, 56.4, 51.0, 46.5,42.3, 37.6, 36.4, 35.7, 30.1, 24.4, 14.7; HRMS calcd. for C₂₆H₂₈BrNO₅S(MH⁺) 568.0758. Found 568.0764.

Allylic Alcohol (23)

To a solution of 22 (20 mg, 0.036 mmol) in hexafluoroisopropanol (0.5mL) was added hydrogen peroxide (30% aq., 0.05 mL) and the resultingsolution was stirred for 15 min until all starting material was consumed(TLC). The reaction mixture was diluted with water (5 ml) and quenchedwith saturated aqueous Na₂SO₃ (2 mL) and the two phases were separated.The aqueous layer was extracted with CH₂Cl₂ (2×5 mL) and the combinedextracts were washed with brine (5 mL), dried (Na₂SO₄) and conc. invacuo to give a pale yellow solid. The crude product was dissolved intoluene (2 mL) and solid NaHCO₃ (15 mg) was added. The mixture washeated at reflux for 2 h until all the intermediate sulfoxide had beenconsumed. The reaction was diluted with water (10 mL) and extracted withCH₂Cl₂ (3×5 mL). The combined extracts were washed with brine (5 mL),dried (Na₂SO₄) and conc. in vacuo to give a pale yellow syrup. The crudeproduct was purified by column chromatography (SiO₂, 50% EtOAc/hexanes)to yield a colorless syrup (14 mg, 87% yield). R_(f)=0.60 (40%EtOAc/Hexanes). IR (thin film) 3446, 2978, 2932, 2868, 1684, 1489, 1435,1321, 1227, 1170, 1147, 1054 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 6.94 (1H,s), 5.77 (1H, d, J=8.8 Hz), 5.30 (1H, dd, J=6.6, 1.5 Hz), 5.02 (Majorrotamer 0.60H, bs), 4.90 (1H, d, J=6.6 Hz), 4.88 (Minor rotamer 0.4H,bs), 4.14 (2H, q, J=7.2 Hz), 3.84 (3H, s), 2.96-2.84 (2H, m), 2.78-2.66(3H, m), 2.60-2.52 (1H, d, J=21 Hz), 2.45-2.41 (1H, m), 1.95-1.87 (4H,m), 1.27 (3H, t, J=7.2 Hz); ¹³C NMR (75 MHz, CDCl₃) Major rotamer:8155.3, 145.9, 143.3, 134.4, 131.3, 126.9, 125.5, 116.2, 113.3, 91.4,66.0, 56.4, 50.3, 47.8, 43.8, 39.3, 37.2, 35.3, 29.7, 14.6; Minorrotamer: δ 155.0, 145.9, 143.3, 134.7, 131.3, 126.8, 125.3, 117.7,113.5, 91.4, 61.7, 56.8, 49.9, 47.8, 41.1, 39.7, 37.7, 34.9, 29.9, 14.7.HRMS calcd. for C₂₀H₂₃BrNO₅ (MH⁺) 436.0757. Found 436.0754.

Codeine (4)

To the allylic alcohol 23 (10 mg, 0.023 mM), in THF (1.5 mL) was addedLiAlH₄ (2M in THF, 0.3 mL) and the solution was stirred at 25° C. for 6h. The reaction mixture was cooled to 0° C. and quenched with drop-wiseaddition of saturated aqueous Na₂SO₄ (0.5 mL). The salts were filteredover a pad of Celite and washed with diethyl ether (10 mL). The combinedorganics were dried (Na₂SO₄) and evaporated in vacuo to yield a paleyellow solid. The crude product was purified (SiO₂, 10% MeOH/CH₂Cl₂) togive codeine (6 mg, 87%). R_(f)=0.21 (10% MeOH/CH₂Cl₂). M.p. 151-153° C.IR (thin film) 3400, 2925, 1501, 1451 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ6.66 (1H, d, J=8.4 Hz), 6.57 (1H, d, J=8.4 Hz), 5.71 (1H, d, J=10 Hz),5.29 (1H, dt, J=10, 2.7 Hz), 4.90 (1H, dd, J=6.6 Hz), 4.18 (1H, m), 3.84(3H, s), 3.36 (1H, m), 3.05 (1H, d, J=18.4 Hz), 2.69 (1H, s), 2.60 (1H,dd, J=12, 4.4 Hz), 2.45 (3H, s), 2.40 (1H, dd, J=12.4, 3.5 Hz), 2.31(1H, dd, J=18.4, 6 Hz), 2.03-2.12 (1H, m), 1.88 (1H, d, J=12.8 Hz); ¹³CNMR (75 MHz, CDCl₃) δ 146.2, 142.0, 133.3, 130.8, 127.9, 126.8, 119.3,112.7, 91.2, 66.3, 58.8, 58.7, 56.1, 46.3, 42.8, 40.4, 35.5, 20.3. HRMScalcd. for C₁₈H₂₂NO₃ (MH⁺) 300.1599. Found 300.1601.

Morphine (5)

To a solution of codeine 4 (8 mg, 0.026 mM) in chloroform (2.5 mL) wasadded boron tribromide (1.0 M in CH₂Cl₂, 0.20 mmol) dropwise over 1 minand the resulting mixture was stirred at room temperature for 20 min. Asolution of NH₄OH (10% aq., 3 mL) was added dropwise at 0° C. Themixture was repeatedly extracted with a solution of 9:1 CH₂Cl₂/EtOH(4×15 mL) and the combined organics were washed with brine (25 mL),dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified(SiO₂, 10% MeOH/CH₂Cl₂) to give morphine 5 (6.5 mg, 86% yield) as awhite solid. R_(f)=0.06 (10% MeOH/CH₂Cl₂). M.p. 251-255° C. IR (thinfilm) 3352, 2924, 1459, 1249 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 6.62 (1H,d, J=8.1 Hz), 6.48 (1H, d, J=8.1 Hz), 5.67 (1H, d, J=9.9 Hz), 5.27 (1H,dt, J=9.9, 2.6 Hz), 4.84 (1H, dd, J=6.3 Hz), 4.18 (1H, m), 3.84 (3H, s),3.36 (1H, m), 3.03 (1H, d, J=18.6 Hz), 2.66 (1H, m), 2.60 (1H, d, J=4.5Hz), 2.47 (1H, dd, J=24.3, 3.6 Hz), 2.46 (1H, s), 2.34 (1H, dd, J=18.9,6.3 Hz), 2.06 (1H, dt, J=12.9, 5.1 Hz), 1.90 (1H, d, J=12.9 Hz). ¹³C NMR(75 MHz, CDCl₃) δ 145.6, 138.1, 132.7, 130.4, 127.9, 125.5, 119.5,116.8, 91.1, 66.2, 58.7, 46.2, 42.7, 42.4, 40.0, 34.8, 20.4. HRMS calcd.for C₁₇H₂₀NO₃ (MH⁺) 286.1443. Found 286.1445.

Example IV

Acid catalyzed hydrolysis of 14 using 2M HCl in dioxane heated at refluxresulted in 24 (93%, 87.5% from 8, structure by X-ray), FIG. 3B thenFIG. 7B. Reductive amination of 24 with MeNH₂ (1.2 eq)/THF (0.25M)/NaBH(OAc)₃ (3.2 eq)/AcOH (5×) at 60° C. proceeded sequentially togive first 25, followed by the carbinolamine 26, and lastly(±)-narwedine 2 (74%) in a single reaction pot.

Compounds 2, 14, 24, 25 and 26 are racemates, but the structures aredrawn in FIGS. 7 A & B (for clarity) as a single enantiomer with theirconfiguration corresponding to that of (−)-galanthamine.

Since (±)-narwedine has been converted into (−)-galanthamine 1 byspontaneous resolution followed by L-Selectride reduction in virtuallyquantitative yield, this completes the synthesis in an overall yield of64.8% which is approximately five times the yield of the currentcommercial process.

Example V

Acid catalyzed hydrolysis of 14 (FIG. 3B) using 2M HCl in dioxane heatedat reflux resulted in 24 (93%, 87.5% from 8, structure by X-ray), FIG.3B then FIG. 7C. Reductive amination of 24 with MeNH₃Cl/NEtPr₂^(i)/dioxane and NaCNBH₃/AcOH at 23° C. for 5 h proceeded to give 27,followed by the treatment with 1M MeSO₃H under dioxane at 80° C. for 40minutes to yield (±)-narwedine 2 (74%) in a single reaction pot.

Compounds 2, 14, 24, and 27 are racemates, but the structures are drawnin FIG. 7C (for clarity) as a single enantiomer with their configurationcorresponding to that of (−)-galanthamine.

Since (±)-narwedine has been converted into (−)-galanthamine 1 byspontaneous resolution followed by L-Selectride reduction in virtuallyquantitative yield, this completes the synthesis in an overall yield of64.8% which is approximately five times the yield of the currentcommercial process.

1. A method of preparing a dihydro-1H-phenanthren-2-one derivative,comprising: a) providing a substituted biphenyl; b) treating saidbiphenyl under conditions so as to create a substituted biphenyl ether;c) treating said ether under conditions so as to create across-conjugated 2,5-cyclohexadienone; and d) treating thecross-conjugated 2,5-cyclohexadienone with a nitroalkane under Henryreaction conditions so as to create a dihydro-1H-phenanthren-2-onederivative.
 2. The method of claim 1, wherein saiddihydro-1H-phenanthren-2-one derivative is a nitroalkene or a β-hydroxynitroalkane.
 3. The method of claim 2, wherein said nitroalkene has thestructure:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups or a protecting group but not H; and R₆ can bealkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups; and wherein said b-hydroxy nitroalkane has the structure:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups or a protecting group but not H; and R₆ can be analkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups.
 4. The method of claim 1, wherein saiddihydro-1H-phenanthren-2-one derivative is in the form of a mixture ofepimers.
 5. The method of claim 2, further comprising treating saidnitroalkene with a reducing agent so as to create nitroalkane.
 6. Themethod of claim 5, wherein said nitroalkane has the structure:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these group or a protecting group, but not H; R₆ can be alkyl,alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups; and R₇ can be alkyl, alkanediyl, alkynyl, aryl, arenediyl,aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or a substitutedversion of any of these groups, or H.
 7. The method of claim 5, whereinsaid nitroalkane is in the form of a mixture of epimers.
 8. The methodof claim 5, further comprising treating said nitroalkane with a reducingagent so as to create a primary amine.
 9. The method of claim 8, whereinsaid amine has the structure:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups or a protecting group, but not H; R₆ can be alkyl,alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups; and R₇ can be alkyl, alkanediyl, alkynyl, aryl, arenediyl,aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or a substitutedversion of any of these groups, or H.
 10. The method of claim 8, furthercomprising treating said primary amine with a reducing agent so as tocreate a secondary amine.
 11. The method of claim 10, wherein saidsecondary amine is the result of intramolecular reductive amination. 12.The method of claim 10, wherein said secondary amine has the structure:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups or a protecting group, or H; and R₇ can be H or analkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups.
 13. The method of claim 10, further comprising treating saidsecondary amine with base so as to create a carbamate derivative. 14.The method of claim 13, wherein said carbamate derivative has thestructure:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups or a protecting group, or H; R₇ is alkyl,alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups, or H; and R₈ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl,aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or a substitutedversion of any of these groups.
 15. The method of claim 10, furthercomprising treating said secondary amine with a carbon-halide, R₈X,where R₈ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups; and X is F, Cl, Br, or I, so as to create atertiary amine.
 16. The method of claim 15, wherein said tertiary aminehas the structure:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups or a protecting group, or H; R₇ is alkyl,alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups, or H; and R₈ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl,aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or a substitutedversion of any of these groups.
 17. The method of claim 13, furthercomprising treating said carbamate derivative with a halohydantoin so asto create a halohydrin.
 18. The method of claim 17, wherein saidhalohydantoin is 2,2 bromo-3,5 dimethylhydantoin and said halohydrin isa bromohydrin.
 19. The method of claim 18, wherein said bromohydrin hasthe structure:

wherein R₁ is an alkyl, aryl, or heteroaryl group or a protecting group,or H; R₇ is alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups, or H; and R₈ is an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups.
 20. The method of claim17, further comprising treating said halohydrin with base so as tocreate an epoxide.
 21. The method of claim 20, wherein said epoxide hasthe structure:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups or a protecting group, or H; R₇ is alkyl,alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups, or H; and R₈ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl,aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or a substitutedversion of any of these groups.
 22. The method of claim 20, furthercomprising treating said epoxide with a reducing agent in the presenceof an organic disulfide so as to create a phenyl sulfide.
 23. The methodof claim 22, wherein said phenyl sulfide has the structure:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups, or H; R₇ is an alkyl, alkanediyl, alkynyl, aryl,arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or asubstituted version of any of these groups, or H; R₈ is an alkyl,alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups; R₉ is alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups; and X is F, Cl, Br, I or equivalent leaving group.24. The method of claim 22, further comprising treating saidphenylsulfide with hydrogen peroxide in the presence ofhexafluoroisopropanol so as to create a sulfoxide.
 25. The method ofclaim 24, wherein said sulfoxide has the structure:

wherein R₁ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups, or H; R₇ is an H or an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups; R₈ is an alkyl,alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups; R₉ is an aryl, or heteroaryl group; and X is F, Cl, Br, I orequivalent leaving group.
 26. The method of claim 24, further comprisingheating said sulfoxide to give an allylic alcohol.
 27. The method ofclaim 26, wherein said allylic alcohol has the structure:

wherein R₁ is an alkyl, aryl, or heteroaryl group or a protecting group,or H; R₇ is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups, or H; R₈ is an alkyl, alkanediyl, alkynyl, aryl,arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or asubstituted version of any of these groups; and X is F, Cl, Br, I orequivalent leaving group.
 28. The method of claim 26, further comprisingtreating said allylic alcohol with a reducing agent so as to createcodeine.
 29. The method of claim 28, further comprising treating saidcodeine with a Lewis acid so as to create morphine.
 30. A composition ofthe formula:

wherein Z is H or R₁O, wherein R₁ is an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups, or H or a protectinggroup; and R₆ can be an alkyl, alkanediyl, alkynyl, aryl, arenediyl,aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or a substitutedversion of any of these groups.
 31. A composition of the formula:

wherein Z is H or R₁O, wherein R₁ is an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups or a protecting group, orH; R₆ can be alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups; and R₇ can be alkyl, alkanediyl, alkynyl, aryl,arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or asubstituted version of any of these groups, or H.
 32. A composition ofthe formula:

wherein Z is H or R₁O, wherein R₁ is an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups or a protecting group, orH; R₆ can be alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups; and R₇ can be alkyl, alkanediyl, alkynyl, aryl,arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or asubstituted version of any of these groups, or H.
 33. A composition ofthe formula:

wherein Z is H or R₁O, wherein R₁ is an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups or a protecting group, orH; R₆ can be alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups; and R₇ can be alkyl, alkanediyl, alkynyl, aryl,arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or asubstituted version of any of these groups, or H.
 34. A composition ofthe formula:

wherein Z is H or R₁O, wherein R₁ is an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups or a protecting group, orH; and R₇ can be H or an alkyl, alkanediyl, alkynyl, aryl, arenediyl,aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or a substitutedversion of any of these groups.
 35. A composition of the formula:

wherein Z is H or R₁O, wherein R₁ is alkyl, alkanediyl, alkynyl, aryl,arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or asubstituted version of any of these groups or a protecting group, or H;R₇ is H or an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups; and R₈ is an alkyl, alkanediyl, alkynyl, aryl,arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or asubstituted version of any of these groups.
 36. A composition of theformula:

wherein Z is H or R₁O, wherein R₁ is an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups or a protecting group, orH; R₇ is H or an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl,heteroaryl, heteroarenediyl, heteroaralkyl, or a substituted version ofany of these groups; and R₈ is an alkyl, alkanediyl, alkynyl, aryl,arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or asubstituted version of any of these groups.
 37. A composition of theformula:

wherein Z is H or R₁O, wherein R₁ is an alkyl, aryl or heteroaryl groupor a protecting group, or H; R₇ is H or an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups; R₈ is an alkyl,alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups; and X is F, Cl, Br, or I.
 38. A composition of the formula:

wherein Z is H or R₁O, wherein R₁ is an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups or a protecting group, orH; R₇ is an H or an alkyl, alkanediyl, alkynyl, aryl, arenediyl,aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or a substitutedversion of any of these groups group; R₈ is an alkyl, alkanediyl,alkynyl, aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl,heteroaralkyl, or a substituted version of any of these groups group; R₉is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups group; and X is F, Cl, Br, or I.
 39. A composition of theformula:

wherein Z is H or R₁O, wherein R₁ is an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups or a protecting group, orH; R₇ is an H or an alkyl, alkanediyl, alkynyl, aryl, arenediyl,aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or a substitutedversion of any of these groups group; R₈ is an alkyl, alkanediyl,alkynyl, aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl,heteroaralkyl, or a substituted version of any of these groups group; R₉is an alkyl, alkanediyl, alkynyl, aryl, arenediyl, aralkyl, heteroaryl,heteroarenediyl, heteroaralkyl, or a substituted version of any of thesegroups group; and X is F, Cl, Br, or I.
 40. The method of claim 20,further comprising treating the epoxide with Grignard reagent underconditions so as to form a epoxide ring opened 6-hydroxy,7-adduct.
 41. Acomposition of the formula:

wherein Z is H or R₁O, wherein R₁ is an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups or a protecting group, orH; R₇ is an H or an alkyl, aryl, or heteroaryl group or the like; R₈ isan alkyl, aryl, or heteroaryl group or the like R₁₀ is an alkyl, aryl,or heteroaryl group or the like (i.e. other groups such as alkanediyl,alkynyl, arenediyl, aralkyl, heteroarenediyl, heteroaralkyl, heteroaryl,alkenyl, alkenediyl, alkynediyl, acyl, alkylidene, non-carbon group, ora substituted version of any of these groups) or H; and X is a halide oran equivalent leaving group.
 42. A composition of the formula:

wherein Z is H or R₁O, wherein R₁ is an alkyl, alkanediyl, alkynyl,aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, ora substituted version of any of these groups or a protecting group, orH; R₇ is an H or an alkyl, alkanediyl, alkynyl, aryl, arenediyl,aralkyl, heteroaryl, heteroarenediyl, heteroaralkyl, or a substitutedversion of any of these groups group; R₈ is an alkyl, alkanediyl,alkynyl, aryl, arenediyl, aralkyl, heteroaryl, heteroarenediyl,heteroaralkyl, or a substituted version of any of these groups group;and X is F, Cl, Br, or I.